cDNAs associated with ataxia-telangiectasia

ABSTRACT

A purified and isolated gene, designated ATM, mutations of which cause ataxia-telangiectasia.

This application is a Continuation-In-Part of U.S. Ser. No. 08/493,092, filed Jun. 21, 1995, which is a Continuation-In-Part of U.S. Ser. No. 08/441,822, filed May 16, 1995.

GRANT SUPPORT

This work was supported in part by grants from the National Institutes of Health, United States-Israel Binational Science Foundation, A-T Medical Research Foundation, A-T Medical Trust, and the A-T Children's Project.

TECHNICAL FIELD

The present invention relates to the determination of the gene sequence, mutations of which cause ataxia-telangiectasia (A-T), designated ATM, and the use of the gene and gene products in detection of carriers of the A-T gene, and preparing native and transgenic organisms in which the gene products encoded by the ATM gene or its homolog in other species are artificially produced, or the expression of the native ATM gene is modified.

BACKGROUND OF THE INVENTION

Ataxia-telangiectasia (A-T) is a progressive genetic disorder affecting the central nervous and immune systems, and involving chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. Studies of the cellular phenotype of A-T have pointed to a defect in a putative system that processes a specific type of DNA damage and initiates a signal transduction pathway controlling replication and repair. For a general review of Ataxia-telangiectasia, reference is hereby made to the review Ataxia-Telangiectasis: Closer to Unraveling the Mystery, Eur. J. Hum. Genet. (Shiloh, 1995) which, along with its cited references, is hereby incorporated by reference.

Despite extensive investigation over the last two decades, A-T has remained a clinical and molecular enigma. A-T is a multi-system disease inherited in an autosomal recessive manner, with a worldwide frequency of 1:100,000 live births and an estimated carrier frequency of 1% in the American population. Notable concentrations of A-T patients outside the United States are in Turkey, Italy and Israel. Israeli A-T patients are Moroccan Jews, Palestinian Arabs, Bedouins and Druzes.

Cerebellar ataxia that gradually develops into general motor dysfunction is the first clinical hallmark and results from progressive loss of Purkinje cells in the cerebellum. Oculocutaneous telangiectasia (dilation of blood vessels) develops in the bulbar conjunctiva and facial skin, and is later accompanied by graying of the hair and atrophic changes in the skin. Somatic growth is retarded in most patients, and ovarian dysgenesis is typical for female patients. Among occasional endocrine abnormalities, insulin-resistant diabetes is predominant, and serum levels of alpha-fetoprotein and carcinoembryonic antigen are elevated. The thymus is either absent or vestigial, and other immunological defects include reduced levels of serum IgA, IgE or IgG2, peripheral lymphopenia, and reduced responses to viral antigens and allogeneic cells, that cause many patients to suffer from recurrent sinopulmonary infections.

Cancer predisposition in A-T is striking: 38% of patients develop malignancies, mainly lymphoreticular neoplasms and leukemias. But, A-T patients manifest acute radiosensitivity and must be treated with reduced radiation doses, and not with radiomimetic chemotherapy. The most common cause of death in A-T, typically during the second or third decade of life, is sinopulmonary infections with or without malignancy.

The complexity of the disease is reflected also in the cellular phenotype. Chromosomal instability is expressed as increased chromosomal breakage and the appearance in lymphocytes of clonal translocations specifically involving the loci of the immune system genes. Such clones may later become predominant when a lymphoreticular malignancy appears. Primary fibroblast lines from A-T patients show accelerated senescence, increased demand for certain growth factors, and defective cytoskeletal structure. Most notable is the abnormal response of A-T cells to ionizing radiation and certain radiomimetic chemicals. While hypersensitive to the cytotoxic and clastogenic effects of these agents, DNA synthesis is inhibited by these agents to a lesser extent than in normal cells. The concomitant lack of radiation-induced cell cycle delay and reduction of radiation-induced elevation of p53 protein are evidence of a defect in a cell cycle checkpoint. Increased intrachromosomal recombination in A-T cells was also noted recently.

Prenatal diagnoses of A-T using cytogenetic analysis or measurements of DNA synthesis have been reported, but these tests are laborious and subject to background fluctuations and, therefore, not widely used.

A-T homozygotes have two defective copies of the A-T gene and are affected with the disease. A-T heterozygotes (carriers) have one normal copy of the gene and one defective copy of the gene and are generally healthy. When two carriers have children, there is a 25% risk in every pregnancy of giving birth to an A-T affected child.

A-T heterozygotes show a significant excess of various malignancies, with a 3- to 4-fold increased risk for all cancers between the ages of 20 and 80, and a 5-fold increased risk of breast cancer in women. These observations turn A-T into a public health problem and add an important dimension to A-T research, particularly to heterozygote identification. Cultured cells from A-T heterozygotes indeed show an intermediate degree of X-ray sensitivity, but the difference from normal cells is not always large enough to warrant using this criterion as a laboratory assay for carrier detection. The main reason for the unreliability of this assay is the various degrees of overlap between A-T heterozygotes and non-heterozygotes with respect to radiosensitivity. Cytogenetic assays for carriers have the same problems as for prenatal diagnosis, they are labor intensive and not always consistent.

The nature of the protein missing in A-T is unknown. Cell fusion studies have established four complementation groups in A-T, designated A, C, D and E, suggesting the probable involvement of at least four genes or four types of mutations in one gene, with inter-allelic complementation. These four groups are clinically indistinguishable and were found to account for 55%, 28%, 14% and 3% of some 80 patients typed to date. In Israel, several Moroccan Jewish patients were assigned to group C, while Palestinian Arab patients were assigned to group A.

The general chromosomal localization of the putative A-T gene(s) has been determined, but not the sequence. An A-T locus containing the A-T(A) mutations was localized by Gatti et al. (1988) to chromosome 11, region q22-23, using linkage analysis. The A-T(C) locus was localized by applicant to the same region of chromosome 11, region q22-23, by linkage analysis of an extended Jewish Moroccan A-T family (Ziv et al., 1991). Further studies, conducted by an international consortium in which applicant participated (McConville et al., 1990; Foroud et al., 1991; Ziv et al., 1992), reconfirmed this localization in a series of studies and gradually narrowed the A-T locus to an interval estimated at 4 centimorgan, which probably contains also the A-T(E) mutations.

A proposed gene for complementation group D is disclosed in U.S. Pat. No. 5,395,767 to Murnane et al., issued Mar. 7, 1995. This sequence was found not to be mutated in any complementation group of A-T. Further, the gene sequence was mapped physically distant from the presumptive A-T locus.

Therefore, in order to better understand the nature and effects of A-T, as well as to more accurately and consistently determine those individuals who may carry the defective gene for A-T, it would be advantageous to isolate and determine the gene sequence, mutations of which are responsible for causing A-T, and utilize this sequence as a basis for detecting carriers of A-T and thereby be able to more beneficially manage the underlying conditions and predispositions of those carriers of the defective gene.

SUMMARY OF THE INVENTION AND ADVANTAGES

According to the present invention, a gene sequence and mutations of this sequence which cause ataxia-telangiectasia (A-T), designated ATM, has been purified, isolated and determined.

The present invention further includes the method for identifying carriers of the defective A-T gene and defective A-T gene products.

Further, the present invention provides transgenic and knockout nonhuman animal and cellular models.

The role of the ATM gene in cancer predisposition makes this gene an important target for screening. The detection of A-T mutation carriers is particularly significant in light of their radiation-sensitivity so that carrier exposure to radiation can be properly monitored and avoided.

BRIEF DESCRIPTION OF THE DRAWINGS

Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:

FIGS. 1A-E illustrate the positional cloning steps to identify the A-T gene(s) wherein FIG. 1A is a high-density marker map of the A-T region on chromosome 11q22-23 (Vanagaite et al., 1995), constructed by generating microsatellite markers within genomic contigs spanning the region and by physical mapping of available markers using the same contigs, the prefix "D11" has been omitted from the marker designations, FDX: the adrenal ferredoxin gene, ACAT: the acetoacetyl-coenzyme A thiolase gene, the stippled box denotes the A-T interval, defined recently by individual recombinants between the markers S1818 and S1819 in a consortium linkage study (Lange et al., 1995), the solid box indicates the two-lod confidence interval for A-T obtained in that study, between S1294 and S384;

FIG. 1B illustrates a part of a YAC contig constructed across this region (Rotman et al., 1994c);

FIG. 1C illustrates part of a cosmid contig spanning the S384-S1818 interval, generated by screening a chromosome-11 specific cosmid library with YAC clones Y16 and Y67, and subsequent contig assembly of the cosmid clones by physical mapping (Shiloh, 1995);

FIG. 1D illustrates products of gene hunting experiments wherein solid boxes denote cDNA fragments obtained by using cosmid and YAC clones for hybrid selection of cDNAs (Lovett et al. 1991; Tagle et al., 1993) from a variety of tissues, open boxes denote putative exons isolated from these cosmids by exon trapping (Church et al., 1993), these sequences hybridized back to specific cosmids (broken lines), which allowed their physical localization to specific subregions of the contig (dotted frames); and

FIG. 1E illustrates a 5.9 kb CDNA clone, designated 7-9, identified in a fibroblast CDNA library using the CDNA fragments and exons in 1D as a probe wherein the open box denotes an open reading frame of 5124 nucleotides, solid lines denote untranslated regions, striped arrowheads denote two Alu elements at the 3' end, and wherein dotted lines drawn between cDNA fragments and exons the CDNA indicate colinearity of sequences.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention consists of a purified, isolated and cloned nucleic acid sequence encoding a gene, designated ATM, mutations in which cause ataxia-telangiectasia and genetic polymorphisms thereof. The nucleic acid can be isolated genomic DNA, cDNA or MRNA. A partial sequence of the ATM gene is set forth in SEQ ID No:1 and in SEQ ID No:3 with the more complete sequence set forth in SEQ ID No:9.

SEQ ID No:1 and SEQ ID No:9 include and extend the cDNA sequence of clone 7-9 in the 5' direction as described herein below. Cosmid clones containing the entire 7-9 sequence are described in Savitsky et al. (1995) and incorporated herein by reference.

SEQ ID No:3 is a 6.5 Kb cloned DNA sequence, designated A-T/4 and represents a sequence of DNA which extends the length of SEQ ID No:1 in the 3' direction. SEQ ID No:3 begins at nucleotide 1432 of SEQ ID No:1 and is identical to SEQ ID No:1 through nucleotide 6556 of SEQ ID No:1 which corresponds to nucleotide 5246 of SEQ ID No:3. From nucleotide 5247 of SEQ ID No:3 through its last nucleotide, SEQ ID No:3 differs from SEQ ID No:1. This difference is thought to reflect alternative splicing creating different protein isoforms.

Polymorphisms are variants in the sequence generally found between different ethnic and geographic locations which, while having a different sequence, produce functionally equivalent gene products.

Current mutation data (as shown in Table 1) indicate that A-T is a disease characterized by considerable allelic heterogenicity. It would not be surprising if there were hundreds (or even thousands) of ATM mutations (as is the case for cystic fibrosis and BRACAI). Mutations imparting defects into the A-T gene can be point mutations, deletions, insertions or rearrangements. The mutations can be present within the nucleotide sequence of the either or both alleles of the ATM gene such that the resulting amino acid sequence of the ATM protein product is altered in one or both copies of the gene product; when present in both copies imparting ataxia-telangiectasia. Alternatively, a mutation event selected from the group consisting of point mutations, deletions, insertions and rearrangements could have occurred within the flanking sequences and/or regulatory sequences of ATM such that regulation of ATM is altered imparting ataxia-telangiectasia.

Table 1 illustrates several mutations in the ATM gene found in A-T patients. Mutations in the ATM gene were found in all of the complementation groups suggesting that ATM is the sole gene responsible for all A-T cases.

                                      TABLE 1                                      __________________________________________________________________________     illustrates several mutations found in A-T patients                            Ethnic/      Complemen-                                                        geographic   tation                                                                               Mutation                 Patient's                          Patient.sup.1                                                                       origin  group.sup.4                                                                          mRNA sequence change                                                                      Protein alteration                                                                       Codon.sup.9                                                                        genotype.sup.10                    __________________________________________________________________________     AT2RO                                                                               Arab    A     Deletion of 11 nt.sup.5                                                                   Frameshift, truncation                                                                   499 Homozygote                         AT3NG                                                                               Dutch   A     Deletion of 3 nt                                                                          Deletion, 1 residue.sup.8                                                                1512                                                                               Compound                                                                       heterozygote                       AT15LA                                                                              Philippine                                                                             A     Insertion, +A                                                                             Frameshift, truncation                                                                   557 Compound                                                                       heterozygote                       AT3LA.sup.2                                                                         African-American                                                                       C     Deletion of 139 nt.sup.6 /                                                                Frameshift, trunction                                                                    1196                                                                               Compound                           AT4LA.sup.2        Deletion of 298 nt.sup.6 heterozygotes                      AT2BR                                                                               Celtic/Irish                                                                           C     Deletion, 9 nt                                                                            Deletion, 3 residues                                                                     1198-                                                                              Homozygote                                                                 1200                                   AT1ABR                                                                              Australian                                                                             E     Deletion, 9 nt                                                                            Deletion, 3 residues                                                                     1198-                                                                              Homozygote                         AT2ABR                                                                              (Irish/British)                    1200                                   AT5BI.sup.2                                                                         Indian/English                                                                         D     Deletion, 6 nt                                                                            Deletion, 2 residues                                                                     1079-                                                                              Compound                           AT6BI.sup.2                             1080                                                                               heterozygotes                      F-2079.sup.3                                                                        Turkish ND    Insertion, +C.sup.5                                                                       Frameshift, truncation                                                                   504 Homozygote                         AT29RM                                                                              Italian ND    Deletion of 175 nt                                                                        Frameshift, truncation                                                                   132 Homozygote                         AT103LO                                                                             Canadian                                                                               ND    Insertion, +A                                                                             Frameshift, truncation                                                                   1635                                                                               Homozygote                         F-596.sup.3                                                                         Palestinian Arab                                                                       ND    Deletion.sup.7                                                                            Truncation                                                                               Most                                                                               Homozygote                                                                 of ORF                                 __________________________________________________________________________      .sup.1 Cell line designation.                                                  .sup.2 Sibling patients in both of whom the same mutation was identified.      .sup.3 Patient expected to be homozygous by descent for an AT mutation.        .sup.4 According to the methods of Jaspers et al. (1988) ND: not               determined.                                                                    .sup.5 An identical sequence change was observed in genomic DNA                .sup.6 No evidence for deletion was observed in genomic DNA. In both           siblings, a normal mRNA was observed in addition to the two deleted            species. The two deleted mRNAs may represent abnormal splicing events          caused by a splice site mutation.                                              .sup.7 Reflects a genomic deletion segregating with the disease in Family      N.                                                                             .sup.8 The deleted serine residue is located within the PI3kinase              signature sequence (1507-1527 of SEQ ID No:2).                                 .sup.9 Numbers refer to residue positions in SEQ ID No:2.                      .sup.10 In all the compound heterozygotes, the second mutation is still        unidentified.                                                            

In cloning the gene for A-T, the strategy used was a common strategy in identifying a disease gene with an unknown protein product known as positional cloning, as is well known in the art. In positional cloning, the target gene is localized to a specific chromosomal region by establishing linkage between the disease and random genetic markers defined by DNA polymorphisms. Definition of the smallest search interval for the gene by genetic analysis is followed by long-range genomic cloning and identification of transcribed sequences within the interval. The disease gene is then identified among these sequences, mainly by searching for mutations in patients.

Several important and long sought disease genes were isolated recently in this way (Collins, 1992; Attree et al., 1992; Berger et al., 1992; Chelly et al., 1993; Vetrie et al., 1993; Trofatter et al., 1993; The Huntington's Disease Collaborative Research Group, 1993; The European Polycystic Kidney Disease Consortium, 1994; Miki et al., 1994).

Two complementary methods were used for the identification of transcribed sequences (gene hunting): hybrid selection based on direct hybridization of genomic DNA with cDNAs from various sources (Parimoo et al., 1991; Lovett et al., 1991); and exon trapping (also called exon amplification), which identifies putative exons in genomic DNA by virtue of their splicing capacity (Church et al., 1993). In hybrid selection experiments, cosmid and YAC clones served to capture cross-hybridizing sequences in cDNA collections from placenta, thymus and fetal brain, using the magnetic bead capture protocol (Morgan et al., 1992; Tagle et al., 1993). In parallel experiments, YAC clones were bound to a solid matrix and used to select cDNA fragments from a heterogeneous cDNA collection representing several human tissues (Parimoo et al., 1993). The cosmids were also used for exon trapping with the pSPL3 vector (Church et al., 1994). The captured cDNA fragments and trapped exons were mapped back to the A-T region by hybridization to several radiation hybrids containing various portions of the 11q22-23 region (Richard et al., 1993; James et al., 1994), and to high-density grids containing all the YACs and cosmids spanning this interval. An extensive transcriptional map of the A-T region was thus constructed (Shiloh et al., 1994).

Pools of adjacent cDNA fragments and exons, expected to converge into the same transcriptional units, were used to screen cDNA libraries. A cluster of 5 cDNA fragments and 3 exons mapped in close proximity to the marker D11S535, where the location score for A-T had peaked (Lange et al., 1995). All these sequences hybridized to the same 5.9 kb of the CDNA clone, 7-9, obtained from a fibroblast CDNA library.

Hybridization of the 7-9 CDNA clone to the radiation hybrid panel indicated that the entire transcript was derived from the chromosome 11 locus. The full sequence of this clone was obtained using a shotgun strategy, and found to contain 5921 bp which includes an open reading frame (ORF) of 5124 nucleotides, a 538 bp 3' untranslated region (3' UTR), and a 259 bp 5' non-coding sequence containing stop codons in all reading frames. (Genbank Accession No. U26455). Two Alu repetitive elements were observed at the 3' end of this clone and in nine smaller clones representing this gene from the same cDNA library. Since no polyadenylation signal was identified in these CDNA clones, their poly(A) tracts were assumed to be associated with the Alu element rather than being authentic poly(A) tails of these transcripts. This assumption was later supported when applicants identified a cDNA clone derived from the same gene in a leukocyte cDNA library, with an alternative 3' UTR containing a typical polyadenylation signal. Alignment of the cDNA with the genomic physical map showed that the corresponding gene is transcribed from centromere to telomere.

Hybridization of a probe containing the entire ORF of clone 7-9 to northern blots from various tissues and cell lines revealed a major transcript of 12 kb in all tissues and cell types examined, and minor species of various sizes in several tissues, possibly representing alternatively spliced transcripts of the corresponding gene or other homologous sequences. Analysis of 12 additional cDNA clones corresponding to this gene indicated a plethora of transcripts generated by multiple alternative splicing combinations. Genomic sequencing later identified the 5' non-coding region of clone 7-9 as sequences of the unspliced adjacent intron. Two other CDNA clones from a leukocyte cDNA library were found to contain this intronic sequence in their 5' ends. These clones may represent either splicing intermediates, or alternatively spliced transcripts of this gene, in which sequences of the adjacent intron were left to serve as an untranslated leader.

The invention further provides a purified protein as encoded by the ATM gene and analogs thereof. A consensus sequence is set forth in SEQ ID No:2 with the complete sequence set forth in SEQ ID No:8. The present invention further provides for mutations in SEQ ID No:2 and SEQ ID No:8 which cause ataxia-telangiectasia, for example, as set forth in Table 1.

The present invention further includes a recombinant protein encoded by the 7-9 clone and/or by SEQ ID No:8. This recombinant protein is isolated and purified by techniques known to those skilled in the art.

An analog will be generally at least 70% homologous over any portion that is functionally relevant. In more preferred embodiments, the homology will be at least 80% and can approach 95% homology to the ATM protein. The amino acid sequence of an analog may differ from that of the ATM protein when at least one residue is deleted, inserted or substituted but the protein remains functional and does not cause A-T. Differences in glycosylation can provide analogs.

The present invention provides an antibody, either polyclonal or monoclonal, which specifically binds to a polypeptide/protein encoded by the ATM gene. In preparing the antibody, the protein (with and without mutations) encoded by the ATM gene and polymorphisms thereof is used as a source of the immunogen. Alternatively, the consensus protein set forth in SEQ ID No:2 or the complete sequence set forth in SEQ ID No:8 can be used. Peptide amino acid sequences isolated from the amino acid sequence as set forth in SEQ ID No:2 and SEQ ID No:8 or mutant peptide sequences can also be used as an immunogen.

The present invention specifically provides antibodies against the following peptides:

HEPANSSASQSTDLC (SEQ ID No:4),

CKRNLSDIDQSFDKV (SEQ ID No:5),

PEDETELHPTLNADDQEC (SEQ ID No:6), and

CKSLASFIKKPFDRGEVESMEDDTNG (SEQ ID No:7).

The antibodies may be either monoclonal or polyclonal. Conveniently, the antibodies may be prepared against a synthetic peptide based on the sequence, or prepared recombinantly by cloning techniques or the natural gene product and/or portions thereof may be isolated and used as the immunogen. Such proteins or peptides can be used to produce antibodies by standard antibody production technology well known to those skilled in the art as described generally in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988.

For producing polyclonal antibodies a host, such as a rabbit or goat, is immunized with the protein or peptide, generally with an adjuvant and, if necessary, coupled to a carrier; antibodies to the protein are collected from the sera.

For producing monoclonal antibodies, the technique involves hyperimmunization of an appropriate donor, generally a mouse, with the protein or peptide fragment and isolation of splenic antibody producing cells. These cells are fused to a cell having immortality, such as a myeloma cell, to provide a fused cell hybrid which has immortality and secretes the required antibody. The cells are then cultured, in bulk, and the monoclonal antibodies harvested from the culture media for use.

The antibody can be bound to a solid support substrate or conjugated with a detectable moiety or be both bound and conjugated as is well known in the art. (For a general discussion of conjugation of fluorescent or enzymatic moieties see Johnstone and Thorpe, Immunochemistry in Practice, Blackwell Scientific Publications, Oxford, 1982.) The binding of antibodies to a solid support substrate is also well known in the art. (see for a general discussion Harlow and Lane Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Publications, New York, 1988) The detectable moieties contemplated with the present invention can include, but are not limited to, fluorescent, metallic, enzymatic and radioactive markers such as biotin, gold, ferritin, alkaline phosphatase, β-galactosidase, peroxidase, urease, fluorescein, rhodamine, tritium, ¹⁴ C and iodination.

The present invention provides vectors comprising an expression control sequence operatively linked to the nucleic acid sequence of the ATM gene, SEQ ID No:9 as well as SEQ ID No:1 and SEQ ID No:3 and portions thereof as well as mutant sequences which lead to the expression of A-T. The present invention further provides host cells, selected from suitable eucaryotic and procaryotic cells, which are transformed with these vectors.

Using the present invention, it is possible to transform host cells, including E. coli, using the appropriate vectors so that they carry either the native or recombinant DNA sequence of the 7-9 cDNA clone or a mutated sequence containing point mutations, deletions, insertions, or rearrangements of DNA as well as the ATM gene, SEQ ID No:9, as well as SEQ ID No:1 and SEQ ID No:3 and portions thereof with mutant sequences which lead to the expression of A-T. Such transformed cells allow the study of the function and the regulation of the A-T gene. Use of recombinantly transformed host cells allows for the study of the mechanisms of A-T and, in particular it will allow for the study of gene function interrupted by the mutations in the A-T gene region.

Vectors are known or can be constructed by those skilled in the art and should contain all expression elements necessary to achieve the desired transcription of the sequences. Other beneficial characteristics can also be contained within the vectors such as mechanisms for recovery of the nucleic acids in a different form. Phagemids are a specific example of such beneficial vectors because they can be used either as plasmids or as bacteriophage vectors. Examples of other vectors include viruses such as bacteriophages, baculoviruses and retroviruses, DNA viruses, cosmids, plasmids, liposomes and other recombination vectors. The vectors can also contain elements for use in either procaryotic or eucaryotic host systems. One of ordinary skill in the art will know which host systems are compatible with a particular vector.

The vectors can be introduced into cells or tissues by any one of a variety of known methods within the art. Such methods can be found generally described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Springs Harbor Laboratory, New York (1992), in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, Md. (1989), Chang et al., Somatic Gene Therapy, CRC Press, Ann Arbor, Mich. (1995), Vega et al., Gene Targeting, CRC Press, Ann Arbor, Mich. (1995) and Gilboa et al (1986) and include, for example, stable or transient transfection, lipofection, electroporation and infection with recombinant viral vectors. Introduction of nucleic acids by infection offers several advantages over the other listed methods. Higher efficiency can be obtained due to their infectious nature. Moreover, viruses are very specialized and typically infect and propagate in specific cell types. Thus, their natural specificity can be used to target the vectors to specific cell types in vivo or within a tissue or mixed culture of cells. Viral vectors can also be modified with specific receptors or ligands to alter target specificity through receptor mediated events.

Recombinant methods known in the art can also be used to achieve the sense, antisense or triplex inhibition of a target nucleic acid. For example, vectors containing antisense nucleic acids can be employed to express protein or antisense message to reduce the expression of the target nucleic acid and therefore its activity.

A specific example of DNA viral vector for introducing and expressing antisense nucleic acids is the adenovirus derived vector Adenop53TK. This vector expresses a herpes virus thymidine kinase (TK) gene for either positive or negative selection and an expression cassette for desired recombinant sequences such as antisense sequences. This vector can be used to infect cells that have an adenovirus receptor which includes most cancers of epithelial origin as well as others. This vector as well as others that exhibit similar desired functions can be used to treat a mixed population of cells include, for example, an in vitro or ex vivo culture of cells, a tissue or a human subject.

Additional features can be added to the vector to ensure its safety and/or enhance its therapeutic efficacy. Such features include, for example, markers that can be used to negatively select against cells infected with the recombinant virus. An example of such a negative selection marker is the TK gene described above that confers sensitivity to the anti-viral gancyclovir. Negative selection is therefore a means by which infection can be controlled because it provides inducible suicide through the addition of antibiotic. Such protection ensures that if, for example, mutations arise that produce altered forms of the viral vector or sequence, cellular transformation will not occur. Features that limit expression to particular cell types can also be included. Such features include, for example, promoter and regulatory elements that are specific for the desired cell type.

Recombinant viral vectors are another example of vectors useful for in vivo expression of a desired nucleic acid because they offer advantages such as lateral infection and targeting specificity. Lateral infection is inherent in the life cycle of, for example, retrovirus and is the process by which a single infected cell produces many progeny virions that bud off and infect neighboring cells. The result is that a large area becomes rapidly infected, most of which was not initially infected by the original viral particles. This is in contrast to vertical-type of infection in which the infectious agent spreads only through daughter progeny. Viral vectors can also be produced that are unable to spread laterally. This characteristic can be useful if the desired purpose is to introduce a specified gene into only a localized number of targeted cells.

As described above, viruses are very specialized infectious agents that have evolved, in many cases, to elude host defense mechanisms. Typically, viruses infect and propagate in specific cell types. The targeting specificity of viral vectors utilizes its natural specificity to specifically target predetermined cell types and thereby introduce a recombinant gene into the infected cell. The vector to be used in the methods of the invention will depend on desired cell type to be targeted. For example, if breast cancer is to be treated, then a vector specific for such epithelial cells should be used. Likewise, if diseases or pathological conditions of the hematopoietic system are to be treated, then a viral vector that is specific for blood cells and their precursors, preferably for the specific type of hematopoietic cell, should be used.

Retroviral vectors can be constructed to function either as infectious particles or to undergo only a single initial round of infection. In the former case, the genome of the virus is modified so that it maintains all the necessary genes, regulatory sequences and packaging signals to synthesize new viral proteins and RNA. Once these molecules are synthesized, the host cell packages the RNA into new viral particles which are capable of undergoing further rounds of infection. The vector's genome is also engineered to encode and express the desired recombinant gene. In the case of non-infectious viral vectors, the vector genome is usually mutated to destroy the viral packaging signal that is required to encapsulate the RNA into viral particles. Without such a signal, any particles that are formed will not contain a genome and therefore cannot proceed through subsequent rounds of infection. The specific type of vector will depend upon the intended application. The actual vectors are also known and readily available within the art or can be constructed by one skilled in the art using well-known methodology.

If viral vectors are used, for example, the procedure can take advantage of their target specificity and consequently, do not have to be administered locally at the diseased site. However, local administration may provide a quicker and more effective treatment, administration can also be performed by, for example, intravenous or subcutaneous injection into the subject. Injection of the viral vectors into a spinal fluid can also be used as a mode of administration, especially in the case of neuro-degenerative diseases. Following injection, the viral vectors will circulate until they recognize host cells with the appropriate target specificity for infection.

Transfection vehicles such as liposomes can also be used to introduce the non-viral vectors described above into recipient cells within the inoculated area. Such transfection vehicles are known by one skilled within the art.

The present invention includes the construction of transgenic and knockout organisms that exhibit the phenotypic manifestations of A-T. The present invention provides for transgenic ATM gene and mutant ATM gene animal and cellular (cell lines) models as well as for knockout ATM models. The transgenic models include those carrying the sequence set forth SEQ ID No:9, or at least, SEQ ID No:1 and/or SEQ ID No:3. These models are constructed using standard methods known in the art and as set forth in U.S. Pat. Nos. 5,387,742, 5,360,735, 5,347,075, 5,298,422, 5,288,846, 5,221,778, 5,175,385, 5,175,384, 5,175,383, 4,736,866 as well as Burke and Olson, (1991), Capecchi, (1989), Davies et al., (1992), Dickinson et al., (1993), Huxley et al., (1991), Jakobovits et al., (1993), Lamb et al., (1993), Rothstein, (1991), Schedl et al., (1993), Strauss et al., (1993). Further, patent applications WO 94/23049, WO 93/14200, WO 94/06908, WO 94/28123 also provide information. See also in general Hogan et al "Manipulating the Mouse Embryo" Cold Spring Harbor Laboratory Press, 2nd Edition (1994).

According to the present invention, there is provided a method for diagnosing and detecting carriers of the defective gene responsible for causing A-T. The present invention further provides methods for detecting normal copies of the ATM gene and its gene product. Carrier detection is especially important since A-T mutations underlie certain cases of cancer predisposition in the general population. Identifying the carriers either by their defective gene or by their missing or defective protein(s) encoded thereby, leads to earlier and more consistent diagnosis of A-T gene carriers. Thus, since carriers of the disease are more likely to be cancer-prone and/or sensitive to therapeutic applications of radiation, better surveillance and treatment protocols can be initiated for them. Conversely, exclusion of A-T heterozygotes from patients undergoing radiotherapy can allow for establishing routinely higher dose schedules for other cancer patients thereby improving the efficacy of their treatment.

Briefly, the methods comprise the steps of obtaining a sample from a test subject, isolating the appropriate test material from the sample and assaying for the target nucleic acid sequence or gene product. The sample can be tissue or bodily fluids from which genetic material and/or proteins are isolated using methods standard in the art. For example, DNA can be isolated from lymphocytes, cells in amniotic fluid and chorionic villi (Llerena et al., 1989).

More specifically, the method of carrier detection is carried out by first obtaining a sample of either cells or bodily fluid from a subject. Convenient methods for obtaining a cellular sample can include collection of either mouth wash fluids or hair roots. A cell sample could be amniotic or placental cells or tissue in the case of a prenatal diagnosis. A crude DNA could be made from the cells (or alternatively proteins isolated) by techniques well known in the art. This isolated target DNA is then used for PCR analysis (or alternatively, Western blot analysis for proteins) with appropriate primers derived from the gene sequence by techniques well known in the art. The PCR product would then be tested for the presence of appropriate sequence variations in order to assess genotypic A-T status of the subject.

The specimen can be assayed for polypeptides/proteins by immunohistochemical and immunocytochemical staining (see generally Stites and Terr, Basic and Clinical Immunology, Appleton and Lange, 1994), ELISA, RIA, immunoblots, Western blotting, immunoprecipitation, functional assays and protein truncation test. In preferred embodiments, Western blotting, functional assays and protein truncation test (Hogervorst et al., 1995) will be used. mRNA complementary to the target nucleic acid sequence can be assayed by in situ hybridization, Northern blotting and reverse transcriptase--polymerase chain reaction. Nucleic acid sequences can be identified by in situ hybridization, Southern blotting, single strand conformational polymorphism, PCR amplification and DNA-chip analysis using specific primers. (Kawasaki, 1990; Sambrook, 1992; Lichter et al, 1990; Orita et al, 1989; Fodor et al., 1993; Pease et al., 1994)

ELISA assays are well known to those skilled in the art. Both polyclonal and monoclonal antibodies can be used in the assays. Where appropriate other immunoassays, such as radioimmunoassays (RIA) can be used as are known to those in the art. Available immunoassays are extensively described in the patent and scientific literature. See, for example, U.S. Pat. Nos. 3,791,932; 3,839,153; 3,850,752; 3,850,578; 3,853,987; 3,867,517; 3,879,262; 3,901,654; 3,935,074; 3,984,533; 3,996,345; 4,034,074; 4,098,876; 4,879,219; 5,011,771 and 5,281,521 as well as Sambrook et al, 1992.

Current mutation data (as shown in Table 1) indicate that A-T is a disease characterized by considerable allelic heterogenicity. It would not be surprising if there were hundreds (or even thousands) of ATM mutations (as is the case for cystic fibrosis and BRACAI). Thus, it will be important for a successful mutation screen to be able to detect all possible nucleotide alterations in the ATM gene, rather than being focused on a limited subset. Methods including direct sequencing of PCR amplified DNA or RNA or DNA chip hybridization (Fodor et al., 1993; Pease et al., 1994) can be applied along with other suitable methods known to those skilled in the art.

In order to use the method of the present invention for diagnostic applications, it is advantageous to include a mechanism for identifying the presence or absence of target polynucleotide sequence (or alternatively proteins). In many hybridization based diagnostic or experimental procedures, a label or tag is used to detect or visualize for the presence or absence of a particular polynucleotide sequence. Typically, oligomer probes are labelled with radioisotopes such as ³² p or ³⁵ S (Sambrook, 1992) which can be detected by methods well known in the art such as autoradiography. Oligomer probes can also be labelled by non-radioactive methods such as chemilluminescent materials which can be detected by autoradiography (Sambrook, 1992). Also, enzyme-substrate based labelling and detection methods can be used. Labelling can be accomplished by mechanisms well known in the art such as end labelling (Sambrook, 1992), chemical labelling, or by hybridization with another labelled oligonucleotide. These methods of labelling and detection are provided merely as examples and are not meant to provide a complete and exhaustive list of all the methods known in the art.

The introduction of a label for detection purposes can be accomplished by attaching the label to the probe prior to hybridization.

An alternative method for practicing the method of the present invention includes the step of binding the target DNA to a solid support prior to the application of the probe. The solid support can be any material capable of binding the target DNA, such as beads or a membranous material such as nitrocellulose or nylon. After the target DNA is bound to the solid support, the probe oligomers is applied.

Functional assays can be used for detection of A-T carriers or affected individuals. For example, if the ATM protein product is shown to have PI 3-kinase biochemical activity which can be assayed in an accessible biological material, such as serum, peripheral leukocytes, etc., then homozygous normal individuals would have approximately normal biological activity and serve as the positive control. A-T carriers would have substantially less than normal biological activity, and affected (i.e. homozygous) individuals would have even less biological activity and serve as a negative control. Such a biochemical assay currently serves as the basis for Tay-Sachs carrier detection.

The present invention also provides a kit for diagnosis and detection of the defective A-T gene. The kit includes a molecular probe complimentary to genetic sequences of the defective gene which causes ataxia-telangiectasia (A-T) andsuitable labels for detecting hybridization of the molecular probe and the defective gene thereby indicating the presence of the defective gene. The molecular probe has a DNA sequence complementary to mutant sequences. Alternatively, the kit can contain reagents and antibodies for detection of mutant proteins.

The above discussion provides a factual basis for the use and identification of the ataxia-telangiectasia gene and gene products and identification of carriers as well as construction of transgenic organisms. The methods used in the present invention can be shown by the following non-limiting example and accompaning figures.

EXAMPLE Materials and Methods

General Methods in Molecular Biology

Standard molecular biology techniques known in the art and not specifically described were generally followed as in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Springs Harbor Laboratory, New York (1989, 1992), and in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, Md. (1989).

Patient and Family Resources

A cell line repository was established containing 230 patient cell lines and 143 cell lines from healthy members of Moroccan Jewish, Palestinian Arab and Druze families. Some of these pedigrees are highly inbred and unusually large (Ziv et al., 1991; Ziv, 1992). In view of the large number of meiotic events required for high-resolution linkage analysis, applicants collaborated with Dr. Carmel McConville (University of Birmingham, UK) and Dr. Richard Gatti (UCLA, Los Angeles, Calif.), who have also established extensive repositories of A-T families. Linkage analysis was conducted on a pool of 176 families.

Definition of the A-T Interval by Genetic Analysis

Studies based only on analysis of Israeli A-T families enabled localization of the A-T(C) gene at 11q22-23 (Ziv, 1991), and confirmed the localization of A-T(A) mutation in Palestinians to the same region (Ziv et al., 1992). Studies with the Birmingham group further narrowed the major A-T interval to 4 centimorgans, between D11S611 and D11S1897 (McConville et al., 1993), and subsequently to 3 centimorgans, between GRIA4 and D11S1897 (Ambrose et al., 1994; McConville et al., 1994) (see also Shiloh, 1995, and FIG. 1).

All these studies were conducted with biallelic markers, whose power is limited by their low polymorphic information content (PIC). The recently discovered microsatellite markers based on variable numbers of tandem simple repeats (Litt and Luty, 1989; Weber and May, 1989) are much more powerful due to their high degree of polymorphism. Microsatellite markers were used to saturate the A-T region using two approaches. The first, was based on physical mapping of microsatellite markers generated by others which were loosely linked to chromosome 11q.

Mapping experiments were conducted using YAC and cosmid contigs which allowed precise, high-resolution localization of DNA sequences in this region of chromosome 11. These experiments led to the localization of 12 microsatellites at the A-T region (Vanagaite et al., 1994a; Vanagaite et al., 1995).

The second approach was based on generating new microsatellites within the YAC contig. A rapid method for the identification of polymorphic CA-repeats in YAC clones was set up (Rotman, 1995) resulting in the generation of twelve new markers within the A-T locus (Vanagaite et al., 1995; Rotman et al., 1995; Rotman et al., 1994b). Hence, the high-density microsatellite map constructed in this manner contained a total of 24 new microsatellite markers and spans the A-T locus and flanking sequences, over a total of six megabases (Vanagaite et al., 1995).

Repeated linkage analysis on the entire cohort of A-T families indicated that the A-T(A) locus was definitely located within a 1.5 megabase region between D11S1819 and D11S1818 (Gatti et al., 1994) as shown in FIG. 1 and in Shiloh (1995), with a clear peak of the cumulative lod score under D11S535 (Lange et al., 1994).

Concomitant with these studies, linkage disequilibrium (LD) analysis of Moroccan-Jewish A-T patients was conducted. LD refers to the non-random association between alleles at two or more polymorphic loci (Chakravarti et al., 1984). LD between disease loci and linked markers is a useful tool for the fine localization of disease genes (Chakravarti et al., 1984; Kerem et al. 1989; Ozelius et al., 1992; Sirugo et al., 1992; Hastbacka et al., 1992; Mitchison et al., 1993). LD is particularly powerful in isolated ethnic groups, where the number of different mutations at a disease locus is likely to be low (Hastbacka et al., 1992; Lehesjoki et al., 1993; Aksentijevitch et al., 1993). Early on, applicants observed very significant LD (p<0.02-p<0.001) between A-T and markers along the D11S1817-D11S927 region in the patients of the sixteen Moroccan-Jewish A-T families identified in Israel (Oskato et al., 1993). Further analysis with the new markers narrowed the peak of linkage disequilibrium to the D11S384-D11S1818 region as shown in FIG. 1.

Haplotype analysis indicated that all of the mutant chromosomes carry the same D11S384-D11S1818 haplotype, suggesting a founder effect for A-T in this community, with one mutation predominating.

Long-range Cloning of the A-T(A)/A-T(C) Region

Cloning the disease locus in a contig (set of overlapping clones) was essential in isolating the A-T disease gene. The entire A-T locus and flanking region in a contig of yeast artificial chromosomes (YACs) was cloned by methods well known in the art (Rotman et al. 1994c; Rotman et al., 1994d). This contig was instrumental in the construction of the microsatellite map of the region (Vanagaite et al., 1995) and subsequently enabled construction of cosmid contigs extending over most of the interval D11S384-D11S1818. Cosmids corresponding to the YAC clones were identified in a chromosome 11-specific cosmid library supplied by Dr. L. Deaven (Los Alamos National Laboratory) and were ordered into contigs by identifying overlaps as shown in FIG. 1.

Isolation of the A-T gene

Transcribed sequences were systematically identified based on two complementary methods:

1. Use of an improved direct selection method based on magnetic bead capture (MBC) of cDNAs corresponding to genomic clones (Morgan et al., 1992; Tagle et al., 1993). In several, large-scale experiments YAC or cosmid DNA was biotinylated and hybridized to PCR-amplified cDNA from thymus, brain and placenta. Genomic DNA-cDNA complexes were captured using streptavidin-coated magnetic beads which was followed with subsequent elution, amplification, and cloning of captured cDNAs. The cDNA inserts were excised from a gel, self-ligated to form concatamers and sonicated to obtain random fragments. These fragments were size fractionated by gel electrophoresis, and the 1.0-1.5 Kb fraction was extracted from the gel and subcloned in a plasmid vector. The end portions of individual clones were sequenced using vector-specific primers, in an automated sequencer (Model 373A, Applied Biosystems), and the sequences were aligned using the AutoAssembler program (Applied Biosystems Division, Perkin-Elmer Corporation). In the final sequence each nucleotide position represents at least 3 independent overlapping readings.

YACs were also used and were no less efficient than cosmids as starting material for MBC, with more than 50% of the products mapping back to the genomic clones. However, when a small panel of radiation hybrids spanning the A-T region was used to test the CDNA fragments, it was found that some clones that hybridized back to the YACs and cosmids were not derived from this region. This pitfall probably stems from limited homology between certain portions of different genes, and points up the necessity to use radiation hybrid mapping when testing the authenticity of the captured sequences, and not to rely solely on cloned DNA for this purpose.

Homology searches in sequence databases showed that only one of the first 105 CDNA fragments mapped to the A-T region was homologous to a sequence previously deposited in one of the databases, as an expressed sequence tag (EST). 2. Exon amplification, also termed "exon trapping" (Duyk et al., 1990; Buckler et al., 1991), is based on cloning genomic fragments into a vector in which exon splice sites are flagged by splicing to their counterpart sites in the vector. This method of gene identification was expected to complement the MBC strategy, since it does not depend on the constitution of cDNA libraries or on the relative abundance of transcripts, and is not affected by the presence of repetitive sequences in the genomic clones. An improved version of this system (Church et al., 1993) that eliminated problems identified in an earlier version, including a high percentage of false positives and the effect of cryptic splice sites was utilized. Each experiment ran a pool of three to five cosmids with an average of two to five exons identified per cosmid. A total of forty five exons were identified.

Sequence analysis and physical mapping indicated that MBC and exon amplification were complementary in identifying transcribed sequences.

The availability of a deep cosmid contig enabled rapid and precise physical localization of the cDNA fragments and captured exons, leading to a detailed transcriptional map of the A-T region.

Both MBC and exon amplification yielded short (100-1000 bp) transcribed sequences. Those sequences were used as anchor points in isolating full-length clones from twenty eight cDNA libraries currently at applicants disposal and which represented a variety of tissues and cell lines.

Initial screening of the cDNA libraries by polymerase chain reaction (PCR) using primer sets derived from individual cDNA fragments or exons aided in the identification of the libraries most likely to yield corresponding cDNA clones.

Large scale screening experiments were carried out in which most of the cDNA fragments and exons were used in large pools. In addition to the mass screening by hybridization, PCR-based screening methods and RACE (rapid amplification of cDNA ends) (Frohman et al., 1988; Frohman et al., 1994) was employed to identify full-length cDNAs.

The above experiments resulted in the identification and isolation of a cDNA clone designated 7-9, the sequence of which is included in SEQ ID No:1 (and SEQ ID No:9), and which is derived from a gene located under the peak of cumulative location score obtained by linkage analysis as shown in FIG. 1. The gene extends over some 300 kilobases (kb) of genomic DNA and codes for two major MRNA species of 12 kb and 10.5 kb in length. The 7-9 clone is 5.9 kb in length and, therefore, is not a full length clone.

An open reading frame of 5124 bp within this cDNA encodes a protein with signature motifs typical of signal transduction proteins, most notably, phosphatidylinositol 3-kinases (PI 3-kinases). PI 3-kinases take part in the complex system responsible for transmitting signals from the outer environment of a cell into the cell. To date, it is not clear whether the protein produced from the 7-9 clone is a part of this transduction system or if it merely contains sequence motifs typical to signal transduction proteins.

Throughout this application various publications and patents are referenced by citation or number. Full citations for the publications referenced are listed below. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation.

Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

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    __________________________________________________________________________     SEQUENCE LISTING                                                               (1) GENERAL INFORMATION:                                                       (iii) NUMBER OF SEQUENCES: 9                                                   (2) INFORMATION FOR SEQ ID NO:1:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 7410 base pairs                                                    (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                        CGACAAATGAGGAATTCAGAATTGGTTCCTTGAGAAATATGATGCAGCTATGTACACGTT60                 GCTTGAGCAACTGTACCAAGAAGAGTCCAAATAAGATTGCATCTGGCTTTTTCCTGCGAT120                TGTTAACATCAAAGCTAATGAATGACATTGCAGATATTTGTAAAAGTTTAGCATCCTTCA180                TCAAAAAGCCATTTGACCGTGGAGAAGTAGAATCAATGGAAGATGATACTAATGGAAATC240                TAATGGAGGTGGAGGATCAGTCATCCATGAATCTATTTAACGATTACCCTGATAGTAGTG300                TTAGTGATGCAAACGAACCTGGAGAGAGCCAAAGTACCATAGGTGCCATTAATCCTTTAG360                CTGAAGAATATCTGTCAAAGCAAGATCTACTTTTCTTAGACATGCTCAAGTTCTTGTGTT420                TGTGTGTAACTACTGCTCAGACCAATACTGTGTCCTTTAGGGCAGCTGATATTCGGAGGA480                AATTGTTAATGTTAATTGATTCTAGCACGCTAGAACCTACCAAATCCCTCCACCTGCATA540                TGTATCTAATGCTTTTAAAGGAGCTTCCTGGAGAAGAGTACCCCTTGCCAATGGAAGATG600                TTCTTGAACTTCTGAAACCACTATCCAATGTGTGTTCTTTGTATCGTCGTGACCAAGATG660                TTTGTAAAACTATTTTAAACCATGTCCTTCATGTAGTGAAAAACCTAGGTCAAAGCAATA720                TGGACTCTGAGAACACAAGGGATGCTCAAGGACAGTTTCTTACAGTAATTGGAGCATTTT780                GGCATCTAACAAAGGAGAGGAAATATATATTCTCTGTAAGAATGGCCCTAGTAAATTGCC840                TTAAAACTTTGCTTGAGGCTGATCCTTATTCAAAATGGGCCATTCTTAATGTAATGGGAA900                AAGACTTTCCTGTAAATGAAGTATTTACACAATTTCTTGCTGACAATCATCACCAAGTTC960                GCATGTTGGCTGCAGAGTCAATCAATAGATTGTTCCAGGACACGAAGGGAGATTCTTCCA1020               GGTTACTGAAAGCACTTCCTTTGAAGCTTCAGCAAACAGCTTTTGAAAATGCATACTTGA1080               AAGCTCAGGAAGGAATGAGAGAAATGTCCCATAGTGCTGAGAACCCTGAAACTTTGGATG1140               AAATTTATAATAGAAAATCTGTTTTACTGACGTTGATAGCTGTGGTTTTATCCTGTAGCC1200               CTATCTGCGAAAAACAGGCTTTGTTTGCCCTGTGTAAATCTGTGAAAGAGAATGGATTAG1260               AACCTCACCTTGTGAAAAAGGTTTTAGAGAAAGTTTCTGAAACTTTTGGATATAGACGTT1320               TAGAAGACTTTATGGCATCTCATTTAGATTATCTGGTTTTGGAATGGCTAAATCTTCAAG1380               ATACTGAATACAACTTATCTTCTTTTCCTTTTATTTTATTAAACTACACAAATATTGAGG1440               ATTTCTATAGATCTTGTTATAAGGTTTTGATTCCACATCTGGTGATTAGAAGTCATTTTG1500               ATGAGGTGAAGTCCATTGCTAATCAGATTCAAGAGGACTGGAAAAGTCTTCTAACAGACT1560               GCTTTCCAAAGATTCTTGTAAATATTCTTCCTTATTTTGCCTATGAGGGTACCAGAGACA1620               GTGGGATGGCACAGCAAAGAGAGACTGCTACCAAGGTCTATGATATGCTTAAAAGTGAAA1680               ACTTATTGGGAAAACAGATTGATCACTTATTCATTAGTAATTTACCAGAGATTGTGGTGG1740               AGTTATTGATGACGTTACATGAGCCAGCAAATTCTAGTGCCAGTCAGAGCACTGACCTCT1800               GTGACTTTTCAGGGGATTTGGATCCTGCTCCTAATCCACCTCATTTTCCATCGCATGTGA1860               TTAAAGCAACATTTGCCTATATCAGCAATTGTCATAAAACCAAGTTAAAAAGCATTTTAG1920               AAATTCTTTCCAAAAGCCCTGATTCCTATCAGAAAATTCTTCTTGCCATATGTGAGCAAG1980               CAGCTGAAACAAATAATGTTTATAAGAAGCACAGAATTCTTAAAATATATCACCTGTTTG2040               TTAGTTTATTACTGAAAGATATAAAAAGTGGCTTAGGAGGAGCTTGGGCCTTTGTTCTTC2100               GAGACGTTATTTATACTTTGATTCACTATATCAACCAAAGGCCTTCTTGTATCATGGATG2160               TGTCATTACGTAGCTTCTCCCTTTGTTGTGACTTATTAAGTCAGGTTTGCCAGACAGCCG2220               TGACTTACTGTAAGGATGCTCTAGAAAACCATCTTCATGTTATTGTTGGTACACTTATAC2280               CCCTTGTGTATGAGCAGGTGGAGGTTCAGAAACAGGTATTGGACTTGTTGAAATACTTAG2340               TGATAGATAACAAGGATAATGAAAACCTCTATATCACGATTAAGCTTTTAGATCCTTTTC2400               CTGACCATGTTGTTTTTAAGGATTTGCGTATTACTCAGCAAAAAATCAAATACAGTAGAG2460               GACCCTTTTCACTCTTGGAGGAAATTAACCATTTTCTCTCAGTAAGTGTTTATGATGCAC2520               TTCCATTGACAAGACTTGAAGGACTAAAGGATCTTCGAAGACAACTGGAACTACATAAAG2580               ATCAGATGGTGGACATTATGAGAGCTTCTCAGGATAATCCGCAAGATGGGATTATGGTGA2640               AACTAGTTGTCAATTTGTTGCAGTTATCCAAGATGGCAATAAACCACACTGGTGAAAAAG2700               AAGTTCTAGAGGCTGTTGGAAGCTGCTTGGGAGAAGTGGGTCCTATAGATTTCTCTACCA2760               TAGCTATACAACATAGTAAAGATGCATCTTATACCAAGGCCCTTAAGTTATTTGAAGATA2820               AAGAACTTCAGTGGACCTTCATAATGCTGACCTACCTGAATAACACACTGGTAGAAGATT2880               GTGTCAAAGTTCGATCAGCAGCTGTTACCTGTTTGAAAAACATTTTAGCCACAAAGACTG2940               GACATAGTTTCTGGGAGATTTATAAGATGACAACAGATCCAATGCTGGCCTATCTACAGC3000               CTTTTAGAACATCAAGAAAAAAGTTTTTAGAAGTACCCAGATTTGACAAAGAAAACCCTT3060               TTGAAGGCCTGGATGATATAAATCTGTGGATTCCTCTAAGTGAAAATCATGACATTTGGA3120               TAAAGACACTGACTTGTGCTTTTTTGGACAGTGGAGGCACAAAATGTGAAATTCTTCAAT3180               TATTAAAGCCAATGTGTGAAGTGAAAACTGACTTTTGTCAGACTGTACTTCCATACTTGA3240               TTCATGATATTTTACTCCAAGATACAAATGAATCATGGAGAAATCTGCTTTCTACACATG3300               TTCAGGGATTTTTCACCAGCTGTCTTCGACACTTCTCGCAAACGAGCCGATCCACAACCC3360               CTGCAAACTTGGATTCAGAGTCAGAGCACTTTTTCCGATGCTGTTTGGATAAAAAATCAC3420               AAAGAACAATGCTTGCTGTTGTGGACTACATGAGAAGACAAAAGAGACCTTCTTCAGGAA3480               CAATTTTTAATGATGCTTTCTGGCTGGATTTAAATTATCTAGAAGTTGCCAAGGTAGCTC3540               AGTCTTGTGCTGCTCACTTTACAGCTTTACTCTATGCAGAAATCTATGCAGATAAGAAAA3600               GTATGGATGATCAAGAGAAAAGAAGTCTTGCATTTGAAGAAGGAAGCCAGAGTACAACTA3660               TTTCTAGCTTGAGTGAAAAAAGTAAAGAAGAAACTGGAATAAGTTTACAGGATCTTCTCT3720               TAGAAATCTACAGAAGTATAGGGGAGCCAGATAGTTTGTATGGCTGTGGTGGAGGGAAGA3780               TGTTACAACCCATTACTAGACTACGAACATATGAACACGAAGCAATGTGGGGCAAAGCCC3840               TAGTAACATATGACCTCGAAACAGCAATCCCCTCATCAACACGCCAGGCAGGAATCATTC3900               AGGCCTTGCAGAATTTGGGACTCTGCCATATTCTTTCCGTCTATTTAAAAGGATTGGATT3960               ATGAAAATAAAGACTGGTGTCCTGAACTAGAAGAACTTCATTACCAAGCAGCATGGAGGA4020               ATATGCAGTGGGACCATTGCACTTCCGTCAGCAAAGAAGTAGAAGGAACCAGTTACCATG4080               AATCATTGTACAATGCTCTACAATCTCTAAGAGACAGAGAATTCTCTACATTTTATGAAA4140               GTCTCAAATATGCCAGAGTAAAAGAAGTGGAAGAGATGTGTAAGCGCAGCCTTGAGTCTG4200               TGTATTCGCTCTATCCCACACTTAGCAGGTTGCAGGCCATTGGAGAGCTGGAAAGCATTG4260               GGGAGCTTTTCTCAAGATCAGTCACACATAGACAACTCTCTGAAGTATATATTAAGTGGC4320               AGAAACACTCCCAGCTTCTCAAGGACAGTGATTTTAGTTTTCAGGAGCCTATCATGGCTC4380               TACGCACAGTCATTTTGGAGATCCTGATGGAAAAGGAAATGGACAACTCACAAAGAGAAT4440               GTATTAAGGACATTCTCACCAAACACCTTGTAGAACTCTCTATACTGGCCAGAACTTTCA4500               AGAACACTCAGCTCCCTGAAAGGGCAATATTTCAAATTAAACAGTACAATTCAGTTAGCT4560               GTGGAGTCTCTGAGTGGCAGCTGGAAGAAGCACAAGTATTCTGGGCAAAAAAGGAGCAGA4620               GTCTTGCCCTGAGTATTCTCAAGCAAATGATCAAGAAGTTGGATGCCAGCTGTGCAGCGA4680               ACAATCCCAGCCTAAAACTTACATACACAGAATGTCTGAGGGTTTGTGGCAACTGGTTAG4740               CAGAAACGTGCTTAGAAAATCCTGCGGTCATCATGCAGACCTATCTAGAAAAGGCAGTAG4800               AAGTTGCTGGAAATTATGATGGAGAAAGTAGTGATGAGCTAAGAAATGGAAAAATGAAGG4860               CATTTCTCTCATTAGCCCGGTTTTCAGATACTCAATACCAAAGAATTGAAAACTACATGA4920               AATCATCGGAATTTGAAAACAAGCAAGCTCTCCTGAAAAGAGCCAAAGAGGAAGTAGGTC4980               TCCTTAGGGAACATAAAATTCAGACAAACAGATACACAGTAAAGGTTCAGCGAGAGCTGG5040               AGTTGGATGAATTAGCCCTGCGTGCACTGAAAGAGGATCGTAAACGCTTCTTATGTAAAG5100               CAGTTGAAAATTATATCAACTGCTTATTAAGTGGAGAAGAACATGATATGTGGGTATTCC5160               GGCTTTGTTCCCTCTGGCTTGAAAATTCTGGAGTTTCTGAAGTCAATGGCATGATGAAGA5220               GAGACGGAATGAAGATTCCAACATATAAATTTTTGCCTCTTATGTACCAATTGGCTGCTA5280               GAATGGGGACCAAGATGATGGGAGGCCTAGGATTTCATGAAGTCCTCAATAATCTAATCT5340               CTAGAATTTCAATGGATCACCCCCATCACACTTTGTTTATTATACTGGCCTTAGCAAATG5400               CAAACAGAGATGAATTTCTGACTAAACCAGAGGTAGCCAGAAGAAGCAGAATAACTAAAA5460               ATGTGCCTAAACAAAGCTCTCAGCTTGATGAGGATCGAACAGAGGCTGCAAATAGAATAA5520               TATGTACTATCAGAAGTAGGAGACCTCAGATGGTCAGAAGTGTTGAGGCACTTTGTGATG5580               CTTATATTATATTAGCAAACTTAGATGCCACTCAGTGGAAGACTCAGAGAAAAGGCATAA5640               ATATTCCAGCAGACCAGCCAATTACTAAACTTAAGAATTTAGAAGATGTTGTTGTCCCTA5700               CTATGGAAATTAAGGTGGACCACACAGGAGAATATGGAAATCTGGTGACTATACAGTCAT5760               TTAAAGCAGAATTTCGCTTAGCAGGAGGTGTAAATTTACCAAAAATAATAGATTGTGTAG5820               GTTCCGATGGCAAGGAGAGGAGACAGCTTGTTAAGGGCCGTGATGACCTGAGACAAGATG5880               CTGTCATGCAACAGGTCTTCCAGATGTGTAATACATTACTGCAGAGAAACACGGAAACTA5940               GGAAGAGGAAATTAACTATCTGTACTTATAAGGTGGTTCCCCTCTCTCAGCGAAGTGGTG6000               TTCTTGAATGGTGCACAGGAACTGTCCCCATTGGTGAATTTCTTGTTAACAATGAAGATG6060               GTGCTCATAAAAGATACAGGCCAAATGATTTCAGTGCCTTTCAGTGCCAAAAGAAAATGA6120               TGGAGGTGCAAAAAAAGTCTTTTGAAGAGAAATATGAAGTCTTCATGGATGTTTGCCAAA6180               ATTTTCAACCAGTTTTCCGTTACTTCTGCATGGAAAAATTCTTGGATCCAGCTATTTGGT6240               TTGAGAAGCGATTGGCTTATACGCGCAGTGTAGCTACTTCTTCTATTGTTGGTTACATAC6300               TTGGACTTGGTGATAGACATGTACAGAATATCTTGATAAATGAGCAGTCAGCAGAACTTG6360               TACATATAGATCTAGGTGTTGCTTTTGAACAGGGCAAAATCCTTCCTACTCCTGAGACAG6420               TTCCTTTTAGACTCACCAGAGATATTGTGGATGGCATGGGCATTACGGGTGTTGAAGGTG6480               TCTTCAGAAGATGCTGTGAGAAAACCATGGAAGTGATGAGAAACTCTCAGGAAACTCTGT6540               TAACCATTGTAGAGGTCCTTCTATATGATCCACTCTTTGACTGGACCATGAATCCTTTGA6600               AAGCTTTGTATTTACAGCAGAGGCCGGAAGATGAAACTGAGCTTCACCCTACTCTGAATG6660               CAGATGACCAAGAATGCAAACGAAATCTCAGTGATATTGACCAGAGTTTCGACAAAGTAG6720               CTGAACGTGTCTTAATGAGACTACAAGAGAAACTGAAAGGAGTGGAAGAAGGCACTGTGC6780               TCAGTGTTGGTGGACAGGTGAATTTGCTCATACAGCAGGCCATAGACCCCAAAAATCTCA6840               GCCGACTTTTCCCAGGATGGAAAGCTTGGGTGTGATCTTCAGTATATGAATTACCCTTTC6900               ATTCAGCCTTTAGAAATTATATTTTAGCCTTTATTTTTAACCTGCCAACATACTTTAAGT6960               AGGGATTAATATTTAAGTGAACTATTGTGGGTTTTTTTGAATGTTGGTTTTAATACTTGA7020               TTTAATCACCACTCAAAAATGTTTTGATGGTCTTAAGGAACATCTCTGCTTTCACTCTTT7080               AGAAATAATGGTCATTCGGGCTGGGCGCAGCGGCTCACGCCTGTAATCCCAGCACTTTGG7140               GAGGCCGAGGTGAGCGGATCACAAGGTCAGGAGTTCGAGACCAGCCTGGCCAAGAGACCA7200               GCCTGGCCAGTATGGTGAAACCCTGTCTCTACTAAAAATACAAAAATTAGCCGAGCATGG7260               TGGCGGGCACCTGTAGTCCCAGCTACTCGAGAGGCTGAGGCAGGAGAATCTCTTGAACCT7320               GGGAGGTGAAGGTTGCTGTGGGCCAAAATCATGCCATTGCACTCCAGCCTGGGTGACAAG7380               AGCGAAACTCCATCTCAAAAAWWAAAAAAA7410                                             (2) INFORMATION FOR SEQ ID NO:2:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 1708 amino acids                                                   (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                        MetThrLeuHisGluProAlaAsnSerSerAlaSerGlnSerThrAsp                               151015                                                                         LeuCysAspPheSerGlyAspLeuAspProAlaProAsnProProHis                               202530                                                                         PheProSerHisValIleLysAlaThrPheAlaTyrIleSerAsnCys                               354045                                                                         HisLysThrLysLeuLysSerIleLeuGluIleLeuSerLysSerPro                               505560                                                                         AspSerTyrGlnLysIleLeuLeuAlaIleCysGluGlnAlaAlaGlu                               65707580                                                                       ThrAsnAsnValTyrLysLysHisArgIleLeuLysIleTyrHisLeu                               859095                                                                         PheValSerLeuLeuLeuLysAspIleLysSerGlyLeuGlyGlyAla                               100105110                                                                      TrpAlaPheValLeuArgAspValIleTyrThrLeuIleHisTyrIle                               115120125                                                                      AsnGlnArgProSerCysIleMetAspValSerLeuArgSerPheSer                               130135140                                                                      LeuCysCysAspLeuLeuSerGlnValCysGlnThrAlaValThrTyr                               145150155160                                                                   CysLysAspAlaLeuGluAsnHisLeuHisValIleValGlyThrLeu                               165170175                                                                      IleProLeuValTyrGluGlnValGluValGlnLysGlnValLeuAsp                               180185190                                                                      LeuLeuLysTyrLeuValIleAspAsnLysAspAsnGluAsnLeuTyr                               195200205                                                                      IleThrIleLysLeuLeuAspProPheProAspHisValValPheLys                               210215220                                                                      AspLeuArgIleThrGlnGlnLysIleLysTyrSerArgGlyProPhe                               225230235240                                                                   SerLeuLeuGluGluIleAsnHisPheLeuSerValSerValTyrAsp                               245250255                                                                      AlaLeuProLeuThrArgLeuGluGlyLeuLysAspLeuArgArgGln                               260265270                                                                      LeuGluLeuHisLysAspGlnMetValAspIleMetArgAlaSerGln                               275280285                                                                      AspAsnProGlnAspGlyIleMetValLysLeuValValAsnLeuLeu                               290295300                                                                      GlnLeuSerLysMetAlaIleAsnHisThrGlyGluLysGluValLeu                               305310315320                                                                   GluAlaValGlySerCysLeuGlyGluValGlyProIleAspPheSer                               325330335                                                                      ThrIleAlaIleGlnHisSerLysAspAlaSerTyrThrLysAlaLeu                               340345350                                                                      LysLeuPheGluAspLysGluLeuGlnTrpThrPheIleMetLeuThr                               355360365                                                                      TyrLeuAsnAsnThrLeuValGluAspCysValLysValArgSerAla                               370375380                                                                      AlaValThrCysLeuLysAsnIleLeuAlaThrLysThrGlyHisSer                               385390395400                                                                   PheTrpGluIleTyrLysMetThrThrAspProMetLeuAlaTyrLeu                               405410415                                                                      GlnProPheArgThrSerArgLysLysPheLeuGluValProArgPhe                               420425430                                                                      AspLysGluAsnProPheGluGlyLeuAspAspIleAsnLeuTrpIle                               435440445                                                                      ProLeuSerGluAsnHisAspIleTrpIleLysThrLeuThrCysAla                               450455460                                                                      PheLeuAspSerGlyGlyThrLysCysGluIleLeuGlnLeuLeuLys                               465470475480                                                                   ProMetCysGluValLysThrAspPheCysGlnThrValLeuProTyr                               485490495                                                                      LeuIleHisAspIleLeuLeuGlnAspThrAsnGluSerTrpArgAsn                               500505510                                                                      LeuLeuSerThrHisValGlnGlyPhePheThrSerCysLeuArgHis                               515520525                                                                      PheSerGlnThrSerArgSerThrThrProAlaAsnLeuAspSerGlu                               530535540                                                                      SerGluHisPhePheArgCysCysLeuAspLysLysSerGlnArgThr                               545550555560                                                                   MetLeuAlaValValAspTyrMetArgArgGlnLysArgProSerSer                               565570575                                                                      GlyThrIlePheAsnAspAlaPheTrpLeuAspLeuAsnTyrLeuGlu                               580585590                                                                      ValAlaLysValAlaGlnSerCysAlaAlaHisPheThrAlaLeuLeu                               595600605                                                                      TyrAlaGluIleTyrAlaAspLysLysSerMetAspAspGlnGluLys                               610615620                                                                      ArgSerLeuAlaPheGluGluGlySerGlnSerThrThrIleSerSer                               625630635640                                                                   LeuSerGluLysSerLysGluGluThrGlyIleSerLeuGlnAspLeu                               645650655                                                                      LeuLeuGluIleTyrArgSerIleGlyGluProAspSerLeuTyrGly                               660665670                                                                      CysGlyGlyGlyLysMetLeuGlnProIleThrArgLeuArgThrTyr                               675680685                                                                      GluHisGluAlaMetTrpGlyLysAlaLeuValThrTyrAspLeuGlu                               690695700                                                                      ThrAlaIleProSerSerThrArgGlnAlaGlyIleIleGlnAlaLeu                               705710715720                                                                   GlnAsnLeuGlyLeuCysHisIleLeuSerValTyrLeuLysGlyLeu                               725730735                                                                      AspTyrGluAsnLysAspTrpCysProGluLeuGluGluLeuHisTyr                               740745750                                                                      GlnAlaAlaTrpArgAsnMetGlnTrpAspHisCysThrSerValSer                               755760765                                                                      LysGluValGluGlyThrSerTyrHisGluSerLeuTyrAsnAlaLeu                               770775780                                                                      GlnSerLeuArgAspArgGluPheSerThrPheTyrGluSerLeuLys                               785790795800                                                                   TyrAlaArgValLysGluValGluGluMetCysLysArgSerLeuGlu                               805810815                                                                      SerValTyrSerLeuTyrProThrLeuSerArgLeuGlnAlaIleGly                               820825830                                                                      GluLeuGluSerIleGlyGluLeuPheSerArgSerValThrHisArg                               835840845                                                                      GlnLeuSerGluValTyrIleLysTrpGlnLysHisSerGlnLeuLeu                               850855860                                                                      LysAspSerAspPheSerPheGlnGluProIleMetAlaLeuArgThr                               865870875880                                                                   ValIleLeuGluIleLeuMetGluLysGluMetAspAsnSerGlnArg                               885890895                                                                      GluCysIleLysAspIleLeuThrLysHisLeuValGluLeuSerIle                               900905910                                                                      LeuAlaArgThrPheLysAsnThrGlnLeuProGluArgAlaIlePhe                               915920925                                                                      GlnIleLysGlnTyrAsnSerValSerCysGlyValSerGluTrpGln                               930935940                                                                      LeuGluGluAlaGlnValPheTrpAlaLysLysGluGlnSerLeuAla                               945950955960                                                                   SerLeuIleLeuLysGlnMetIleLysLysLeuAspAlaSerCysAla                               965970975                                                                      AlaAsnAsnProSerLeuLysLeuThrTyrThrGluCysLeuArgVal                               980985990                                                                      CysGlyAsnTrpLeuAlaGluThrCysLeuGluAsnProAlaValIle                               99510001005                                                                    MetGlnThrTyrLeuGluLysAlaValGluValAlaGlyAsnTyrAsp                               101010151020                                                                   GlyGluSerSerAspGluLeuArgAsnGlyLysMetLysAlaPheLeu                               1025103010351040                                                               SerLeuAlaArgPheSerAspThrGlnTyrGlnArgIleGluAsnTyr                               104510501055                                                                   MetLysSerSerGluPheGluAsnLysGlnAlaLeuLeuLysArgAla                               106010651070                                                                   LysGluGluValGlyLeuLeuArgGluHisLysIleGlnThrAsnArg                               107510801085                                                                   TyrThrValLysValGlnArgGluLeuGluLeuAspGluLeuAlaLeu                               109010951100                                                                   ArgAlaLeuLysGluAspArgLysArgPheLeuCysLysAlaValGlu                               1105111011151120                                                               AsnTyrIleAsnCysLeuLeuSerGlyGluGluHisAspMetTrpVal                               112511301135                                                                   PheArgLeuCysSerLeuTrpLeuGluAsnSerGlyValSerGluVal                               114011451150                                                                   AsnGlyMetMetLysArgAspGlyMetLysIleProThrTyrLysPhe                               115511601165                                                                   LeuProLeuMetTyrGlnLeuAlaAlaArgMetGlyThrLysMetMet                               117011751180                                                                   GlyGlyLeuGlyPheHisGluValLeuAsnAsnLeuIleSerArgIle                               1185119011951200                                                               SerMetAspHisProHisHisThrLeuPheIleIleLeuAlaLeuAla                               120512101215                                                                   AsnAlaAsnArgAspGluPheLeuThrLysProGluValAlaArgArg                               122012251230                                                                   SerArgIleThrLysAsnValProLysGlnSerSerGlnLeuAspGlu                               123512401245                                                                   AspArgThrGluAlaAlaAsnArgIleIleCysThrIleArgSerArg                               125012551260                                                                   ArgProGlnMetValArgSerValGluAlaLeuCysAspAlaTyrIle                               1265127012751280                                                               IleLeuAlaAsnLeuAspAlaThrGlnTrpLysThrGlnArgLysGly                               128512901295                                                                   IleAsnIleProAlaAspGlnProIleThrLysLeuLysAsnLeuGlu                               130013051310                                                                   AspValValValProThrMetGluIleLysValAspHisThrGlyGlu                               131513201325                                                                   TyrGlyAsnLeuValThrIleGlnSerPheLysAlaGluPheArgLeu                               133013351340                                                                   AlaGlyGlyValAsnLeuProLysIleIleAspCysValGlySerAsp                               1345135013551360                                                               GlyLysGluArgArgGlnLeuValLysGlyArgAspAspLeuArgGln                               136513701375                                                                   AspAlaValMetGlnGlnValPheGlnMetCysAsnThrLeuLeuGln                               138013851390                                                                   ArgAsnThrGluThrArgLysArgLysLeuThrIleCysThrTyrLys                               139514001405                                                                   ValValProLeuSerGlnArgSerGlyValLeuGluTrpCysThrGly                               141014151420                                                                   ThrValProIleGlyGluPheLeuValAsnAsnGluAspGlyAlaHis                               1425143014351440                                                               LysArgTyrArgProAsnAspPheSerAlaPheGlnCysGlnLysLys                               144514501455                                                                   MetMetGluValGlnLysLysSerPheGluGluLysTyrGluValPhe                               146014651470                                                                   MetAspValCysGlnAsnPheGlnProValPheArgTyrPheCysMet                               147514801485                                                                   GluLysPheLeuAspProAlaIleTrpPheGluLysArgLeuAlaTyr                               149014951500                                                                   ThrArgSerValAlaThrSerSerIleValGlyTyrIleLeuGlyLeu                               1505151015151520                                                               GlyAspArgHisValGlnAsnIleLeuIleAsnGluGlnSerAlaGlu                               152515301535                                                                   LeuValHisIleAspLeuGlyValAlaPheGluGlnGlyLysIleLeu                               154015451550                                                                   ProThrProGluThrValProPheArgLeuThrArgAspIleValAsp                               155515601565                                                                   GlyMetGlyIleThrGlyValGluGlyValPheArgArgCysCysGlu                               157015751580                                                                   LysThrMetGluValMetArgAsnSerGlnGluThrLeuLeuThrIle                               1585159015951600                                                               ValGluValLeuLeuTyrAspProLeuPheAspTrpThrMetAsnPro                               160516101615                                                                   LeuLysAlaLeuTyrLeuGlnGlnArgProGluAspGluThrGluLeu                               162016251630                                                                   HisProThrLeuAsnAlaAspAspGlnGluCysLysArgAsnLeuSer                               163516401645                                                                   AspIleAspGlnSerPheAspLysValAlaGluArgValLeuMetArg                               165016551660                                                                   LeuGlnGluLysLeuLysGlyValGluGluGlyThrValLeuSerVal                               1665167016751680                                                               GlyGlyGlnValAsnLeuLeuIleGlnGlnAlaIleAspProLysAsn                               168516901695                                                                   LeuSerArgLeuPheProGlyTrpLysAlaTrpVal                                           17001705                                                                       (2) INFORMATION FOR SEQ ID NO:3:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 6525 base pairs                                                    (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                        ATATTGAGGATTTCTATAGATCTTGTTATAAGGTTTTGATTCCACATCTGGTGATTAGAA60                 GTCATTTTGATGAGGTGAAGTCCATTGCTAATCAGATTCAAGAGGACTGGAAAAGTCTTC120                TAACAGACTGCTTTCCAAAGATTCTTGTAAATATTCTTCCTTATTTTGCCTATGAGGGTA180                CCAGAGACAGTGGGATGGCACAGCAAAGAGAGACTGCTACCAAGGTCTATGATATGCTTA240                AAAGTGAAAACTTATTGGGAAAACAGTCTACAGGTTGGCTGCATAGAAGAAAAAGGTAGA300                GTTATTTATAATCTTGTAAATCTTGGACTTTGAGTCATCTATTTTCTTTTACAGTCATCG360                AATACTTTTGGAAATAAGATTGATCACTTATTCATTAGTAATTTACCAGAGATTGTGGTG420                GAGTTATTGATGACGTTACATGAGCCAGCAAATTCTAGTGCCAGTCAGAGCACTGACCTC480                TGTGACTTTTCAGGGGATTTGGATCCTGCTCCTAATCCACCTCATTTTCCATCGCATGTG540                ATTAAAGCAACATTTGCCTATATCAGCAATTGTCATAAAACCAAGTTAAAAAGCATTTTA600                GAAATTCTTTCCAAAAGCCCTGATTCCTATCAGAAAATTCTTCTTGCCATATGTGAGCAA660                GCAGCTGAAACAAATAATGTTTATAAGAAGCACAGAATTCTTAAAATATATCACCTGTTT720                GTTAGTTTATTACTGAAAGATATAAAAAGTGGCTTAGGAGGAGCTTGGGCCTTTGTTCTT780                CGAGACGTTATTTATACTTTGATTCACTATATCAACCAAAGGCCTTCTTGTATCATGGAT840                GTGTCATTACGTAGCTTCTCCCTTTGTTGTGACTTATTAAGTCAGGTTTGCCAGACAGCC900                GTGACTTACTGTAAGGATGCTCTAGAAAACCATCTTCATGTTATTGTTGGTACACTTATA960                CCCCTTGTGTATGAGCAGGTGGAGGTTCAGAAACAGGTATTGGACTTGTTGAAATACTTA1020               GTGATAGATAACAAGGATAATGAAAACCTCTATATCACGATTAAGCTTTTAGATCCTTTT1080               CCTGACCATGTTGTTTTTAAGGATTTGCGTATTACTCAGCAAAAAATCAAATACAGTAGA1140               GGACCCTTTTCACTCTTGGAGGAAATTAACCATTTTCTCTCAGTAAGTGTTTATGATGCA1200               CTTCCATTGACAAGACTTGAAGGACTAAAGGATCTTCGAAGACAACTGGAACTACATAAA1260               GATCAGATGGTGGACATTATGAGAGCTTCTCAGGATAATCCGCAAGATGGGATTATGGTG1320               AAACTAGTTGTCAATTTGTTGCAGTTATCCAAGATGGCAATAAACCACACTGGTGAAAAA1380               GAAGTTCTAGAGGCTGTTGGAAGCTGCTTGGGAGAAGTGGGTCCTATAGATTTCTCTACC1440               ATAGCTATACAACATAGTAAAGATGCATCTTATACCAAGGCCCTTAAGTTATTTGAAGAT1500               AAAGAACTTCAGTGGACCTTCATAATGCTGACCTACCTGAATAACACACTGGTAGAAGAT1560               TGTGTCAAAGTTCGATCAGCAGCTGTTACCTGTTTGAAAAACATTTTAGCCACAAAGACT1620               GGACATAGTTTCTGGGAGATTTATAAGATGACAACAGATCCAATGCTGGCCTATCTACAG1680               CCTTTTAGAACATCAAGAAAAAAGTTTTTAGAAGTACCCAGATTTGACAAAGAAAACCCT1740               TTTGAAGGCCTGGATGATATAAATCTGTGGATTCCTCTAAGTGAAAATCATGACATTTGG1800               ATAAAGACACTGACTTGTGCTTTTTTGGACAGTGGAGGCACAAAATGTGAAATTCTTCAA1860               TTATTAAAGCCAATGTGTGAAGTGAAAACTGACTTTTGTCAGACTGTACTTCCATACTTG1920               ATTCATGATATTTTACTCCAAGATACAAATGAATCATGGAGAAATCTGCTTTCTACACAT1980               GTTCAGGGATTTTTCACCAGCTGTCTTCGACACTTCTCGCAAACGAGCCGATCCACAACC2040               CCTGCAAACTTGGATTCAGAGTCAGAGCACTTTTTCCGATGCTGTTTGGATAAAAAATCA2100               CAAAGAACAATGCTTGCTGTTGTGGACTACATGAGAAGACAAAAGAGACCTTCTTCAGGA2160               ACAATTTTTAATGATGCTTTCTGGCTGGATTTAAATTATCTAGAAGTTGCCAAGGTAGCT2220               CAGTCTTGTGCTGCTCACTTTACAGCTTTACTCTATGCAGAAATCTATGCAGATAAGAAA2280               AGTATGGATGATCAAGAGAAAAGAAGTCTTGCATTTGAAGAAGGAAGCCAGAGTACAACT2340               ATTTCTAGCTTGAGTGAAAAAAGTAAAGAAGAAACTGGAATAAGTTTACAGGATCTTCTC2400               TTAGAAATCTACAGAAGTATAGGGGAGCCAGATAGTTTGTATGGCTGTGGTGGAGGGAAG2460               ATGTTACAACCCATTACTAGACTACGAACATATGAACACGAAGCAATGTGGGGCAAAGCC2520               CTAGTAACATATGACCTCGAAACAGCAATCCCCTCATCAACACGCCAGGCAGGAATCATT2580               CAGGCCTTGCAGAATTTGGGACTCTGCCATATTCTTTCCGTCTATTTAAAAGGATTGGAT2640               TATGAAAATAAAGACTGGTGTCCTGAACTAGAAGAACTTCATTACCAAGCAGCATGGAGG2700               AATATGCAGTGGGACCATTGCACTTCCGTCAGCAAAGAAGTAGAAGGAACCAGTTACCAT2760               GAATCATTGTACAATGCTCTACAATCTCTAAGAGACAGAGAATTCTCTACATTTTATGAA2820               AGTCTCAAATATGCCAGAGTAAAAGAAGTGGAAGAGATGTGTAAGCGCAGCCTTGAGTCT2880               GTGTATTCGCTCTATCCCACACTTAGCAGGTTGCAGGCCATTGGAGAGCTGGAAAGCATT2940               GGGGAGCTTTTCTCAAGATCAGTCACACATAGACAACTCTCTGAAGTATATATTAAGTGG3000               CAGAAACACTCCCAGCTTCTCAAGGACAGTGATTTTAGTTTTCAGGAGCCTATCATGGCT3060               CTACGCACAGTCATTTTGGAGATCCTGATGGAAAAGGAAATGGACAACTCACAAAGAGAA3120               TGTATTAAGGACATTCTCACCAAACACCTTGTAGAACTCTCTATACTGGCCAGAACTTTC3180               AAGAACACTCAGCTCCCTGAAAGGGCAATATTTCAAATTAAACAGTACAATTCAGTTAGC3240               TGTGGAGTCTCTGAGTGGCAGCTGGAAGAAGCACAAGTATTCTGGGCAAAAAAGGAGCAG3300               AGTCTTGCCCTGAGTATTCTCAAGCAAATGATCAAGAAGTTGGATGCCAGCTGTGCAGCG3360               AACAATCCCAGCCTAAAACTTACATACACAGAATGTCTGAGGGTTTGTGGCAACTGGTTA3420               GCAGAAACGTGCTTAGAAAATCCTGCGGTCATCATGCAGACCTATCTAGAAAAGGCAGTA3480               GAAGTTGCTGGAAATTATGATGGAGAAAGTAGTGATGAGCTAAGAAATGGAAAAATGAAG3540               GCATTTCTCTCATTAGCCCGGTTTTCAGATACTCAATACCAAAGAATTGAAAACTACATG3600               AAATCATCGGAATTTGAAAACAAGCAAGCTCTCCTGAAAAGAGCCAAAGAGGAAGTAGGT3660               CTCCTTAGGGAACATAAAATTCAGACAAACAGATACACAGTAAAGGTTCAGCGAGAGCTG3720               GAGTTGGATGAATTAGCCCTGCGTGCACTGAAAGAGGATCGTAAACGCTTCTTATGTAAA3780               GCAGTTGAAAATTATATCAACTGCTTATTAAGTGGAGAAGAACATGATATGTGGGTATTC3840               CGACTTTGTTCCCTCTGGCTTGAAAATTCTGGAGTTTCTGAAGTCAATGGCATGATGAAG3900               AGAGACGGAATGAAGATTCCAACATATAAATTTTTGCCTCTTATGTACCAATTGGCTGCT3960               AGAATGGGGACCAAGATGATGGGAGGCCTAGGATTTCATGAAGTCCTCAATAATCTAATC4020               TCTAGAATTTCAATGGATCACCCCCATCACACTTTGTTTATTATACTGGCCTTAGCAAAT4080               GCAAACAGAGATGAATTTCTGACTAAACCAGAGGTAGCCAGAAGAAGCAGAATAACTAAA4140               AATGTGCCTAAACAAAGCTCTCAGCTTGATGAGGATCGAACAGAGGCTGCAAATAGAATA4200               ATATGTACTATCAGAAGTAGGAGACCTCAGATGGTCAGAAGTGTTGAGGCACTTTGTGAT4260               GCTTATATTATATTAGCAAACTTAGATGCCACTCAGTGGAAGACTCAGAGAAAAGGCATA4320               AATATTCCAGCAGACCAGCCAATTACTAAACTTAAGAATTTAGAAGATGTTGTTGTCCCT4380               ACTATGGAAATTAAGGTGGACCACACAGGAGAATATGGAAATCTGGTGACTATACAGTCA4440               TTTAAAGCAGAATTTCGCTTAGCAGGAGGTGTAAATTTACCAAAAATAATAGATTGTGTA4500               GGTTCCGATGGCAAGGAGAGGAGACAGCTTGTTAAGGGCCGTGATGACCTGAGACAAGAT4560               GCTGTCATGCAACAGGTCTTCCAGATGTGTAATACATTACTGCAGAGAAACACGGAAACT4620               AGGAAGAGGAAATTAACTATCTGTACTTATAAGGTGGTTCCCCTCTCTCAGCGAAGTGGT4680               GTTCTTGAATGGTGCACAGGAACTGTCCCCATTGGTGAATTTCTTGTTAACAATGAAGAT4740               GGTGCTCATAAAAGATACAGGCCAAATGATTTCAGTGCCTTTCAGTGCCAAAAGAAAATG4800               ATGGAGGTGCAAAAAAAGTCTTTTGAAGAGAAATATGAAGTCTTCATGGATGTTTGCCAA4860               AATTTTCAACCAGTTTTCCGTTACTTCTGCATGGAAAAATTCTTGGATCCAGCTATTTGG4920               TTTGAGAAGCGATTGGCTTATACGCGCAGTGTAGCTACTTCTTCTATTGTTGGTTACATA4980               CTTGGACTTGGTGATAGACATGTACAGAATATCTTGATAAATGAGCAGTCAGCAGAACTT5040               GTACATATAGATCTAGGTGTTGCTTTTGAACAGGGCAAAATCCTTCCTACTCCTGAGACA5100               GTTCCTTTTAGACTCACCAGAGATATTGTGGATGGCATGGGCATTACGGGTGTTGAAGGT5160               GTCTTCAGAAGATGCTGTGAGAAAACCATGGAAGTGATGAGAAACTCTCAGGAAACTCTG5220               TTAACCATTGTAGAGGTAAAGTATTTTATAAGGAAGACTTTATTTTTTTTCTTACCAGGT5280               AGACTGTGTATCTCATCAGGAAGTCACTGATGTGAAGAGCACTGCTTCATTTTAACATAG5340               GGGGATGTGGCTGGGCAGCAGAAAGGAGGAGATTGTGCACTTAGCCTTTTCACACATCCA5400               AAAATACTGGTTTAGAAATGCCTTCAGCCCCCTTGAGTTTCTTGGAATGTTAGAGCATTG5460               TAAGTAGTCTCTAGTTTTCAATTCATAAATCAATTCTTTGACATTTAGATATTCCATATG5520               GTATTATTATTTTTAGAATGGTTTCCATTAGGGTTTACGAAAAATCAGAAATTTATATCT5580               CCTCTTTCCCTGCTCAGGTTCAGAACTAATTAGTCAGACAAAATGGAGATCAAAATTGGT5640               CAGCATCATTACTAGAGGGACATGGCTTAGGAATTGAGGGCCAAGACTAGTTTACCTGCT5700               GGTGCTACCCTCAAGTACCCTCCCTGCTGTCTTAACTTTGGGACAAGCTCACCCTGAATA5760               GGGGTTGGGCCTGCAGAGCAAACACATGTAATCAGGATCACTGCCTTGTCTTGATCCAGG5820               GCAGAAAAAAGGAAGTCAAACAAATTTCAGTGTCTGTGCTGTTAGTACCTATGCCAGTCA5880               TTCACCAATCTGGTAAGGGTATGTGAGACAAGAAATCAGGAGTGTGGCCTCCCCAGGGAA5940               GCATGGCAGGTAGAGTGCAGTATGGGCTTGCCACTTTTCCACTACTCAGCTTTTCTTCCT6000               TTAACCTGATTTATGTTGGACTGGCTGCATGTTAGTATTACTTTTACTGCATTTAAAAAA6060               CATTGATGCTGATCAAATTCAAACCAGGTTTCTAGAGATGGGGCAGGAATATGTGCATTT6120               TTAAAAATCTCTCCTACTGTTCCACTAGGATATGAGAACTGTCTTAATTCATTGGCATTA6180               ACCATTAAGCCTGTGGTCAATAAGGGTGGGCCTTTATCCCTTGGAAGATGAGTAACAGTC6240               CATCAGGGTGGTCCTGTGTGCACCTTTATGAACCGAGGCATCTTTATAGATCTCCTTTGG6300               ACTGCAGGTGGTAATACAGATTTTGCTACAAGGAGTTTGCTGAAATAGGTCCCAATAATA6360               CGTTGGTAAAATTAAATCCAAGNCTGTGCTATTCCCAAGGTTAAAAATACATTCTTTTTT6420               CTTTTACCGATTTCAAATTCTGTTCATACATGTTGTCATTTGTTACAGTTTGCCATTGGT6480               TCTGCAGTAAGAATAAATGATAAGAAAATAAAAAAAAAAAAAAAA6525                              (2) INFORMATION FOR SEQ ID NO:4:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 15 amino acids                                                     (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                        HisGluProAlaAsnSerSerAlaSerGlnSerThrAspLeuCys                                  151015                                                                         (2) INFORMATION FOR SEQ ID NO:5:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 15 amino acids                                                     (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                        CysLysArgAsnLeuSerAspIleAspGlnSerPheAspLysVal                                  151015                                                                         (2) INFORMATION FOR SEQ ID NO:6:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 18 amino acids                                                     (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                        ProGluAspGluThrGluLeuHisProThrLeuAsnAlaAspAspGln                               151015                                                                         GluCys                                                                         (2) INFORMATION FOR SEQ ID NO:7:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 26 amino acids                                                     (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                        CysLysSerLeuAlaSerPheIleLysLysProPheAspArgGlyGlu                               151015                                                                         ValGluSerMetGluAspAspThrAsnGly                                                 2025                                                                           (2) INFORMATION FOR SEQ ID NO:8:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 3056 amino acids                                                   (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                        MetSerLeuValLeuAsnAspLeuLeuIleCysCysArgGlnLeuGlu                               151015                                                                         HisAspArgAlaThrGluArgLysLysGluValGluLysPheLysArg                               202530                                                                         LeuIleArgAspProGluThrIleLysHisLeuAspArgHisSerAsp                               354045                                                                         SerLysGlnGlyLysTyrLeuAsnTrpAspAlaValPheArgPheLeu                               505560                                                                         GlnLysTyrIleGlnLysGluThrGluCysLeuArgIleAlaLysPro                               65707580                                                                       AsnValSerAlaSerThrGlnAlaSerArgGlnLysLysMetGlnGlu                               859095                                                                         IleSerSerLeuValLysTyrPheIleLysCysAlaAsnArgArgAla                               100105110                                                                      ProArgLeuLysCysGlnGluLeuLeuAsnTyrIleMetAspThrVal                               115120125                                                                      LysAspSerSerAsnGlyAlaIleTyrGlyAlaAspCysSerAsnIle                               130135140                                                                      LeuLeuLysAspIleLeuSerValArgLysTyrTrpCysGluIleSer                               145150155160                                                                   GlnGlnGlnTrpLeuGluLeuPheSerValTyrPheArgLeuTyrLeu                               165170175                                                                      LysProSerGlnAspValHisArgValLeuValAlaArgIleIleHis                               180185190                                                                      AlaValThrLysGlyCysCysSerGlnThrAspGlyLeuAsnSerLys                               195200205                                                                      PheLeuAspPhePheSerLysAlaIleGlnCysAlaArgGlnGluLys                               210215220                                                                      SerSerSerGlyLeuAsnHisIleLeuAlaAlaLeuThrIlePheLeu                               225230235240                                                                   LysThrLeuAlaValAsnPheArgIleArgValCysGluLeuGlyAsp                               245250255                                                                      GluIleLeuProThrLeuValTyrIleTrpThrGlnHisArgLeuAsn                               260265270                                                                      AspSerLeuLysGluValIleIleGluLeuPheGlnLeuGlnIleTyr                               275280285                                                                      IleHisHisProLysGlyAlaLysThrGlnGluLysGlyAlaTyrGlu                               290295300                                                                      SerThrLysTrpArgSerIleLeuTyrAsnLeuTyrAspLeuLeuVal                               305310315320                                                                   AsnGluIleSerHisIleGlySerArgGlyLysTyrSerSerGlyPhe                               325330335                                                                      ArgAsnIleAlaValLysGluAsnLeuIleGluLeuMetAlaAspIle                               340345350                                                                      CysHisGlnValPheAsnGluAspThrArgSerLeuGluIleSerGln                               355360365                                                                      SerTyrThrThrThrGlnArgGluSerSerAspTyrSerValProCys                               370375380                                                                      LysArgLysLysIleGluLeuGlyTrpGluValIleLysAspHisLeu                               385390395400                                                                   GlnLysSerGlnAsnAspPheAspLeuValProTrpLeuGlnIleAla                               405410415                                                                      ThrGlnLeuIleSerLysTyrProAlaSerLeuProAsnCysGluLeu                               420425430                                                                      SerProLeuLeuMetIleLeuSerGlnLeuLeuProGlnGlnArgHis                               435440445                                                                      GlyGluArgThrProTyrValLeuArgCysLeuThrGluValAlaLeu                               450455460                                                                      CysGlnAspLysArgSerAsnLeuGluSerSerGlnLysSerAspLeu                               465470475480                                                                   LeuLysLeuTrpAsnLysIleTrpCysIleThrPheArgGlyIleSer                               485490495                                                                      SerGluGlnLysGlnAlaGluAsnPheGlyLeuLeuGlyAlaIleIle                               500505510                                                                      GlnGlySerLeuValGluValAspArgGluPheTrpLysLeuPheThr                               515520525                                                                      GlySerAlaCysArgProSerCysProAlaValCysCysLeuThrLeu                               530535540                                                                      AlaLeuThrThrSerIleValProGlyAlaValLysMetGlyIleGlu                               545550555560                                                                   GlnAsnMetCysGluValAsnArgSerPheSerLeuLysGluSerIle                               565570575                                                                      MetLysTrpLeuLeuPheTyrGlnLeuGluGlyAspLeuGluAsnSer                               580585590                                                                      ThrGluValProProIleLeuHisSerAsnPheProHisLeuValLeu                               595600605                                                                      GluLysIleLeuValSerLeuThrMetLysAsnCysLysAlaAlaMet                               610615620                                                                      AsnPhePheGlnSerValProGluCysGluHisHisHisLysAspLys                               625630635640                                                                   GluGluLeuSerPheSerGluValGluGluLeuPheLeuGlnThrThr                               645650655                                                                      PheAspLysMetAspPheLeuThrIleValArgGluCysGlyIleGlu                               660665670                                                                      LysHisGlnSerSerIleGlyPheSerValHisGlnAsnLeuLysGlu                               675680685                                                                      SerLeuAspArgCysLeuLeuGlyLeuSerGluGlnLeuLeuAsnAsn                               690695700                                                                      TyrSerSerGluIleThrAsnSerGluThrLeuValArgCysSerArg                               705710715720                                                                   LeuLeuValGlyValLeuGlyCysTyrCysTyrMetGlyValIleAla                               725730735                                                                      GluGluGluAlaTyrLysSerGluLeuPheGlnLysAlaAsnSerLeu                               740745750                                                                      MetGlnCysAlaGlyGluSerIleThrLeuPheLysAsnLysThrAsn                               755760765                                                                      GluGluPheArgIleGlySerLeuArgAsnMetMetGlnLeuCysThr                               770775780                                                                      ArgCysLeuSerAsnCysThrLysLysSerProAsnLysIleAlaSer                               785790795800                                                                   GlyPhePheLeuArgLeuLeuThrSerLysLeuMetAsnAspIleAla                               805810815                                                                      AspIleCysLysSerLeuAlaSerPheIleLysLysProPheAspArg                               820825830                                                                      GlyGluValGluSerMetGluAspAspThrAsnGlyAsnLeuMetGlu                               835840845                                                                      ValGluAspGlnSerSerMetAsnLeuPheAsnAspTyrProAspSer                               850855860                                                                      SerValSerAspAlaAsnGluProGlyGluSerGlnSerThrIleGly                               865870875880                                                                   AlaIleAsnProLeuAlaGluGluTyrLeuSerLysGlnAspLeuLeu                               885890895                                                                      PheLeuAspMetLeuLysPheLeuCysLeuCysValThrThrAlaGln                               900905910                                                                      ThrAsnThrValSerPheArgAlaAlaAspIleArgArgLysLeuLeu                               915920925                                                                      MetLeuIleAspSerSerThrLeuGluProThrLysSerLeuHisLeu                               930935940                                                                      HisMetTyrLeuMetLeuLeuLysGluLeuProGlyGluGluTyrPro                               945950955960                                                                   LeuProMetGluAspValLeuGluLeuLeuLysProLeuSerAsnVal                               965970975                                                                      CysSerLeuTyrArgArgAspGlnAspValCysLysThrIleLeuAsn                               980985990                                                                      HisValLeuHisValValLysAsnLeuGlyGlnSerAsnMetAspSer                               99510001005                                                                    GluAsnThrArgAspAlaGlnGlyGlnPheLeuThrValIleGlyAla                               101010151020                                                                   PheTrpHisLeuThrLysGluArgLysTyrIlePheSerValArgMet                               1025103010351040                                                               AlaLeuValAsnCysLeuLysThrLeuLeuGluAlaAspProTyrSer                               104510501055                                                                   LysTrpAlaIleLeuAsnValMetGlyLysAspPheProValAsnGlu                               106010651070                                                                   ValPheThrGlnPheLeuAlaAspAsnHisHisGlnValArgMetLeu                               107510801085                                                                   AlaAlaGluSerIleAsnArgLeuPheGlnAspThrLysGlyAspSer                               109010951100                                                                   SerArgLeuLeuLysAlaLeuProLeuLysLeuGlnGlnThrAlaPhe                               1105111011151120                                                               GluAsnAlaTyrLeuLysAlaGlnGluGlyMetArgGluMetSerHis                               112511301135                                                                   SerAlaGluAsnProGluThrLeuAspGluIleTyrAsnArgLysSer                               114011451150                                                                   ValLeuLeuThrLeuIleAlaValValLeuSerCysSerProIleCys                               115511601165                                                                   GluLysGlnAlaLeuPheAlaLeuCysLysSerValLysGluAsnGly                               117011751180                                                                   LeuGluProHisLeuValLysLysValLeuGluLysValSerGluThr                               1185119011951200                                                               PheGlyTyrArgArgLeuGluAspPheMetAlaSerHisLeuAspTyr                               120512101215                                                                   LeuValLeuGluTrpLeuAsnLeuGlnAspThrGluTyrAsnLeuSer                               122012251230                                                                   SerPheProPheIleLeuLeuAsnTyrThrAsnIleGluAspPheTyr                               123512401245                                                                   ArgSerCysTyrLysValLeuIleProHisLeuValIleArgSerHis                               125012551260                                                                   PheAspGluValLysSerIleAlaAsnGlnIleGlnGluAspTrpLys                               1265127012751280                                                               SerLeuLeuThrAspCysPheProLysIleLeuValAsnIleLeuPro                               128512901295                                                                   TyrPheAlaTyrGluGlyThrArgAspSerGlyMetAlaGlnGlnArg                               130013051310                                                                   GluThrAlaThrLysValTyrAspMetLeuLysSerGluAsnLeuLeu                               131513201325                                                                   GlyLysGlnIleAspHisLeuPheIleSerAsnLeuProGluIleVal                               133013351340                                                                   ValGluLeuLeuMetThrLeuHisGluProAlaAsnSerSerAlaSer                               1345135013551360                                                               GlnSerThrAspLeuCysAspPheSerGlyAspLeuAspProAlaPro                               136513701375                                                                   AsnProProHisPheProSerHisValIleLysAlaThrPheAlaTyr                               138013851390                                                                   IleSerAsnCysHisLysThrLysLeuLysSerIleLeuGluIleLeu                               139514001405                                                                   SerLysSerProAspSerTyrGlnLysIleLeuLeuAlaIleCysGlu                               141014151420                                                                   GlnAlaAlaGluThrAsnAsnValTyrLysLysHisArgIleLeuLys                               1425143014351440                                                               IleTyrHisLeuPheValSerLeuLeuLeuLysAspIleLysSerGly                               144514501455                                                                   LeuGlyGlyAlaTrpAlaPheValLeuArgAspValIleTyrThrLeu                               146014651470                                                                   IleHisTyrIleAsnGlnArgProSerCysIleMetAspValSerLeu                               147514801485                                                                   ArgSerPheSerLeuCysCysAspLeuLeuSerGlnValCysGlnThr                               149014951500                                                                   AlaValThrTyrCysLysAspAlaLeuGluAsnHisLeuHisValIle                               1505151015151520                                                               ValGlyThrLeuIleProLeuValTyrGluGlnValGluValGlnLys                               152515301535                                                                   GlnValLeuAspLeuLeuLysTyrLeuValIleAspAsnLysAspAsn                               154015451550                                                                   GluAsnLeuTyrIleThrIleLysLeuLeuAspProPheProAspHis                               155515601565                                                                   ValValPheLysAspLeuArgIleThrGlnGlnLysIleLysTyrSer                               157015751580                                                                   ArgGlyProPheSerLeuLeuGluGluIleAsnHisPheLeuSerVal                               1585159015951600                                                               SerValTyrAspAlaLeuProLeuThrArgLeuGluGlyLeuLysAsp                               160516101615                                                                   LeuArgArgGlnLeuGluLeuHisLysAspGlnMetValAspIleMet                               162016251630                                                                   ArgAlaSerGlnAspAsnProGlnAspGlyIleMetValLysLeuVal                               163516401645                                                                   ValAsnLeuLeuGlnLeuSerLysMetAlaIleAsnHisThrGlyGlu                               165016551660                                                                   LysGluValLeuGluAlaValGlySerCysLeuGlyGluValGlyPro                               1665167016751680                                                               IleAspPheSerThrIleAlaIleGlnHisSerLysAspAlaSerTyr                               168516901695                                                                   ThrLysAlaLeuLysLeuPheGluAspLysGluLeuGlnTrpThrPhe                               170017051710                                                                   IleMetLeuThrTyrLeuAsnAsnThrLeuValGluAspCysValLys                               171517201725                                                                   ValArgSerAlaAlaValThrCysLeuLysAsnIleLeuAlaThrLys                               173017351740                                                                   ThrGlyHisSerPheTrpGluIleTyrLysMetThrThrAspProMet                               1745175017551760                                                               LeuAlaTyrLeuGlnProPheArgThrSerArgLysLysPheLeuGlu                               176517701775                                                                   ValProArgPheAspLysGluAsnProPheGluGlyLeuAspAspIle                               178017851790                                                                   AsnLeuTrpIleProLeuSerGluAsnHisAspIleTrpIleLysThr                               179518001805                                                                   LeuThrCysAlaPheLeuAspSerGlyGlyThrLysCysGluIleLeu                               181018151820                                                                   GlnLeuLeuLysProMetCysGluValLysThrAspPheCysGlnThr                               1825183018351840                                                               ValLeuProTyrLeuIleHisAspIleLeuLeuGlnAspThrAsnGlu                               184518501855                                                                   SerTrpArgAsnLeuLeuSerThrHisValGlnGlyPhePheThrSer                               186018651870                                                                   CysLeuArgHisPheSerGlnThrSerArgSerThrThrProAlaAsn                               187518801885                                                                   LeuAspSerGluSerGluHisPhePheArgCysCysLeuAspLysLys                               189018951900                                                                   SerGlnArgThrMetLeuAlaValValAspTyrMetArgArgGlnLys                               1905191019151920                                                               ArgProSerSerGlyThrIlePheAsnAspAlaPheTrpLeuAspLeu                               192519301935                                                                   AsnTyrLeuGluValAlaLysValAlaGlnSerCysAlaAlaHisPhe                               194019451950                                                                   ThrAlaLeuLeuTyrAlaGluIleTyrAlaAspLysLysSerMetAsp                               195519601965                                                                   AspGlnGluLysArgSerLeuAlaPheGluGluGlySerGlnSerThr                               197019751980                                                                   ThrIleSerSerLeuSerGluLysSerLysGluGluThrGlyIleSer                               1985199019952000                                                               LeuGlnAspLeuLeuLeuGluIleTyrArgSerIleGlyGluProAsp                               200520102015                                                                   SerLeuTyrGlyCysGlyGlyGlyLysMetLeuGlnProIleThrArg                               202020252030                                                                   LeuArgThrTyrGluHisGluAlaMetTrpGlyLysAlaLeuValThr                               203520402045                                                                   TyrAspLeuGluThrAlaIleProSerSerThrArgGlnAlaGlyIle                               205020552060                                                                   IleGlnAlaLeuGlnAsnLeuGlyLeuCysHisIleLeuSerValTyr                               2065207020752080                                                               LeuLysGlyLeuAspTyrGluAsnLysAspTrpCysProGluLeuGlu                               208520902095                                                                   GluLeuHisTyrGlnAlaAlaTrpArgAsnMetGlnTrpAspHisCys                               210021052110                                                                   ThrSerValSerLysGluValGluGlyThrSerTyrHisGluSerLeu                               211521202125                                                                   TyrAsnAlaLeuGlnSerLeuArgAspArgGluPheSerThrPheTyr                               213021352140                                                                   GluSerLeuLysTyrAlaArgValLysGluValGluGluMetCysLys                               2145215021552160                                                               ArgSerLeuGluSerValTyrSerLeuTyrProThrLeuSerArgLeu                               216521702175                                                                   GlnAlaIleGlyGluLeuGluSerIleGlyGluLeuPheSerArgSer                               218021852190                                                                   ValThrHisArgGlnLeuSerGluValTyrIleLysTrpGlnLysHis                               219522002205                                                                   SerGlnLeuLeuLysAspSerAspPheSerPheGlnGluProIleMet                               221022152220                                                                   AlaLeuArgThrValIleLeuGluIleLeuMetGluLysGluMetAsp                               2225223022352240                                                               AsnSerGlnArgGluCysIleLysAspIleLeuThrLysHisLeuVal                               224522502255                                                                   GluLeuSerIleLeuAlaArgThrPheLysAsnThrGlnLeuProGlu                               226022652270                                                                   ArgAlaIlePheGlnIleLysGlnTyrAsnSerValSerCysGlyVal                               227522802285                                                                   SerGluTrpGlnLeuGluGluAlaGlnValPheTrpAlaLysLysGlu                               229022952300                                                                   GlnSerLeuAlaLeuSerIleLeuLysGlnMetIleLysLysLeuAsp                               2305231023152320                                                               AlaSerCysAlaAlaAsnAsnProSerLeuLysLeuThrTyrThrGlu                               232523302335                                                                   CysLeuArgValCysGlyAsnTrpLeuAlaGluThrCysLeuGluAsn                               234023452350                                                                   ProAlaValIleMetGlnThrTyrLeuGluLysAlaValGluValAla                               235523602365                                                                   GlyAsnTyrAspGlyGluSerSerAspGluLeuArgAsnGlyLysMet                               237023752380                                                                   LysAlaPheLeuSerLeuAlaArgPheSerAspThrGlnTyrGlnArg                               2385239023952400                                                               IleGluAsnTyrMetLysSerSerGluPheGluAsnLysGlnAlaLeu                               240524102415                                                                   LeuLysArgAlaLysGluGluValGlyLeuLeuArgGluHisLysIle                               242024252430                                                                   GlnThrAsnArgTyrThrValLysValGlnArgGluLeuGluLeuAsp                               243524402445                                                                   GluLeuAlaLeuArgAlaLeuLysGluAspArgLysArgPheLeuCys                               245024552460                                                                   LysAlaValGluAsnTyrIleAsnCysLeuLeuSerGlyGluGluHis                               2465247024752480                                                               AspMetTrpValPheArgLeuCysSerLeuTrpLeuGluAsnSerGly                               248524902495                                                                   ValSerGluValAsnGlyMetMetLysArgAspGlyMetLysIlePro                               250025052510                                                                   ThrTyrLysPheLeuProLeuMetTyrGlnLeuAlaAlaArgMetGly                               251525202525                                                                   ThrLysMetMetGlyGlyLeuGlyPheHisGluValLeuAsnAsnLeu                               253025352540                                                                   IleSerArgIleSerMetAspHisProHisHisThrLeuPheIleIle                               2545255025552560                                                               LeuAlaLeuAlaAsnAlaAsnArgAspGluPheLeuThrLysProGlu                               256525702575                                                                   ValAlaArgArgSerArgIleThrLysAsnValProLysGlnSerSer                               258025852590                                                                   GlnLeuAspGluAspArgThrGluAlaAlaAsnArgIleIleCysThr                               259526002605                                                                   IleArgSerArgArgProGlnMetValArgSerValGluAlaLeuCys                               261026152620                                                                   AspAlaTyrIleIleLeuAlaAsnLeuAspAlaThrGlnTrpLysThr                               2625263026352640                                                               GlnArgLysGlyIleAsnIleProAlaAspGlnProIleThrLysLeu                               264526502655                                                                   LysAsnLeuGluAspValValValProThrMetGluIleLysValAsp                               266026652670                                                                   HisThrGlyGluTyrGlyAsnLeuValThrIleGlnSerPheLysAla                               267526802685                                                                   GluPheArgLeuAlaGlyGlyValAsnLeuProLysIleIleAspCys                               269026952700                                                                   ValGlySerAspGlyLysGluArgArgGlnLeuValLysGlyArgAsp                               2705271027152720                                                               AspLeuArgGlnAspAlaValMetGlnGlnValPheGlnMetCysAsn                               272527302735                                                                   ThrLeuLeuGlnArgAsnThrGluThrArgLysArgLysLeuThrIle                               274027452750                                                                   CysThrTyrLysValValProLeuSerGlnArgSerGlyValLeuGlu                               275527602765                                                                   TrpCysThrGlyThrValProIleGlyGluPheLeuValAsnAsnGlu                               277027752780                                                                   AspGlyAlaHisLysArgTyrArgProAsnAspPheSerAlaPheGln                               2785279027952800                                                               CysGlnLysLysMetMetGluValGlnLysLysSerPheGluGluLys                               280528102815                                                                   TyrGluValPheMetAspValCysGlnAsnPheGlnProValPheArg                               282028252830                                                                   TyrPheCysMetGluLysPheLeuAspProAlaIleTrpPheGluLys                               283528402845                                                                   ArgLeuAlaTyrThrArgSerValAlaThrSerSerIleValGlyTyr                               285028552860                                                                   IleLeuGlyLeuGlyAspArgHisValGlnAsnIleLeuIleAsnGlu                               2865287028752880                                                               GlnSerAlaGluLeuValHisIleAspLeuGlyValAlaPheGluGln                               288528902895                                                                   GlyLysIleLeuProThrProGluThrValProPheArgLeuThrArg                               290029052910                                                                   AspIleValAspGlyMetGlyIleThrGlyValGluGlyValPheArg                               291529202925                                                                   ArgCysCysGluLysThrMetGluValMetArgAsnSerGlnGluThr                               293029352940                                                                   LeuLeuThrIleValGluValLeuLeuTyrAspProLeuPheAspTrp                               2945295029552960                                                               ThrMetAsnProLeuLysAlaLeuTyrLeuGlnGlnArgProGluAsp                               296529702975                                                                   GluThrGluLeuHisProThrLeuAsnAlaAspAspGlnGluCysLys                               298029852990                                                                   ArgAsnLeuSerAspIleAspGlnSerPheAspLysValAlaGluArg                               299530003005                                                                   ValLeuMetArgLeuGlnGluLysLeuLysGlyValGluGluGlyThr                               301030153020                                                                   ValLeuSerValGlyGlyGlnValAsnLeuLeuIleGlnGlnAlaIle                               3025303030353040                                                               AspProLysAsnLeuSerArgLeuPheProGlyTrpLysAlaTrpVal                               304530503055                                                                   (2) INFORMATION FOR SEQ ID NO:9:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 9870 base pairs                                                    (B) TYPE: nucleic acid                                                         (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                        ATCTGCGCTGCCTTCCGAGTGCAGTGAGGCCCTTCCGAGTGCAGTGAGGCATACATCACA60                 ATTTGGAATTATGCATTGGTTTATCAATTTACTTGTTTATTGTCACCCTGCTGCCCAGAT120                ATGACTTCATGAGGACAGTGATGTGTGTTCTGAAATTGTGAACCATGAGTCTAGTACTTA180                ATGATCTGCTTATCTGCTGCCGTCAACTAGAACATGATAGAGCTACAGAACGAAAGAAAG240                AAGTTGAGAAATTTAAGCGCCTGATTCGAGATCCTGAAACAATTAAACATCTAGATCGGC300                ATTCAGATTCCAAACAAGGAAAATATTTGAATTGGGATGCTGTTTTTAGATTTTTACAGA360                AATATATTCAGAAAGAAACAGAATGTCTGAGAATAGCAAAACCAAATGTATCAGCCTCAA420                CACAAGCCTCCAGGCAGAAAAAGATGCAGGAAATCAGTAGTTTGGTCAAATACTTCATCA480                AATGTGCAAACAGAAGAGCACCTAGGCTAAAATGTCAAGAACTCTTAAATTATATCATGG540                ATACAGTGAAAGATTCATCTAATGGTGCTATTTACGGAGCTGATTGTAGCAACATACTAC600                TCAAAGACATTCTTTCTGTGAGAAAATACTGGTGTGAAATATCTCAGCAACAGTGGTTAG660                AATTGTTCTCTGTGTACTTCAGGCTCTATCTGAAACCTTCACAAGATGTTCATAGAGTTT720                TAGTGGCTAGAATAATTCATGCTGTTACCAAAGGATGCTGTTCTCAGACTGACGGATTAA780                ATTCCAAATTTTTGGACTTTTTTTCCAAGGCTATTCAGTGTGCGAGACAAGAAAAGAGCT840                CTTCAGGTCTAAATCATATCTTAGCAGCTCTTACTATCTTCCTCAAGACTTTGGCTGTCA900                ACTTTCGAATTCGAGTGTGTGAATTAGGAGATGAAATTCTTCCCACTTTGGTTTATATTT960                GGACTCAACATAGGCTTAATGATTCTTTAAAAGAAGTCATTATTGAATTATTTCAACTGC1020               AAATTTATATCCATCATCCGAAAGGAGCCAAAACCCAAGAAAAAGGTGCTTATGAATCAA1080               CAAAATGGAGAAGTATTTTATACAACTTATATGATCTGCTAGTGAATGAGATAAGTCATA1140               TAGGAAGTAGAGGAAAGTATTCTTCAGGATTTCGTAATATTGCCGTCAAAGAAAATTTGA1200               TTGAATTGATGGCAGATATCTGTCACCAGGTTTTTAATGAAGATACCAGATCCTTGGAGA1260               TTTCTCAATCTTACACTACTACACAAAGAGAATCTAGTGATTACAGTGTCCCTTGCAAAA1320               GGAAGAAAATAGAACTAGGCTGGGAAGTAATAAAAGATCACCTTCAGAAGTCACAGAATG1380               ATTTTGATCTTGTGCCTTGGCTACAGATTGCAACCCAATTAATATCAAAGTATCCTGCAA1440               GTTTACCTAACTGTGAGCTGTCTCCATTACTGATGATACTATCTCAGCTTCTACCCCAAC1500               AGCGACATGGGGAACGTACACCATATGTGTTACGATGCCTTACGGAAGTTGCATTGTGTC1560               AAGACAAGAGGTCAAACCTAGAAAGCTCACAAAAGTCAGATTTATTAAAACTCTGGAATA1620               AAATTTGGTGTATTACCTTTCGTGGTATAAGTTCTGAGCAAAAACAAGCTGAAAACTTTG1680               GCTTACTTGGAGCCATAATTCAGGGTAGTTTAGTTGAGGTTGACAGAGAATTCTGGAAGT1740               TATTTACTGGGTCAGCCTGCAGACCTTCATGTCCTGCAGTATGCTGTTTGACTTTGGCAC1800               TGACCACCAGTATAGTTCCAGGAGCGGTAAAAATGGGAATAGAGCAAAATATGTGTGAAG1860               TAAATAGAAGCTTTTCTTTAAAGGAATCAATAATGAAATGGCTCTTATTCTATCAGTTAG1920               AGGGTGACTTAGAAAATAGCACAGAAGTGCCTCCAATTCTTCACAGTAATTTTCCTCATC1980               TTGTACTGGAGAAAATTCTTGTGAGTCTCACTATGAAAAACTGTAAAGCTGCAATGAATT2040               TTTTCCAAAGCGTGCCAGAATGTGAACACCACCACAAAGATAAAGAAGAACTTTCATTCT2100               CAGAAGTAGAAGAACTATTTCTTCAGACAACTTTTGACAAGATGGACTTTTTAACCATTG2160               TGAGAGAATGTGGTATAGAAAAGCACCAGTCCAGTATTGGCTTCTCTGTCCACCAGAATC2220               TCAAGGAATCACTGGATCGCTGTCTTCTGGGATTATCAGAACAGCTTCTGAATAATTACT2280               CATCTGAGATTACAAATTCAGAAACTCTTGTCCGGTGTTCACGTCTTTTGGTGGGTGTCC2340               TTGGCTGCTACTGTTACATGGGTGTAATAGCTGAAGAGGAAGCATATAAGTCAGAATTAT2400               TCCAGAAAGCCAACTCTCTAATGCAATGTGCAGGAGAAAGTATCACTCTGTTTAAAAATA2460               AGACAAATGAGGAATTCAGAATTGGTTCCTTGAGAAATATGATGCAGCTATGTACACGTT2520               GCTTGAGCAACTGTACCAAGAAGAGTCCAAATAAGATTGCATCTGGCTTTTTCCTGCGAT2580               TGTTAACATCAAAGCTAATGAATGACATTGCAGATATTTGTAAAAGTTTAGCATCCTTCA2640               TCAAAAAGCCATTTGACCGTGGAGAAGTAGAATCAATGGAAGATGATACTAATGGAAATC2700               TAATGGAGGTGGAGGATCAGTCATCCATGAATCTATTTAACGATTACCCTGATAGTAGTG2760               TTAGTGATGCAAACGAACCTGGAGAGAGCCAAAGTACCATAGGTGCCATTAATCCTTTAG2820               CTGAAGAATATCTGTCAAAGCAAGATCTACTTTTCTTAGACATGCTCAAGTTCTTGTGTT2880               TGTGTGTAACTACTGCTCAGACCAATACTGTGTCCTTTAGGGCAGCTGATATTCGGAGGA2940               AATTGTTAATGTTAATTGATTCTAGCACGCTAGAACCTACCAAATCCCTCCACCTGCATA3000               TGTATCTAATGCTTTTAAAGGAGCTTCCTGGAGAAGAGTACCCCTTGCCAATGGAAGATG3060               TTCTTGAACTTCTGAAACCACTATCCAATGTGTGTTCTTTGTATCGTCGTGACCAAGATG3120               TTTGTAAAACTATTTTAAACCATGTCCTTCATGTAGTGAAAAACCTAGGTCAAAGCAATA3180               TGGACTCTGAGAACACAAGGGATGCTCAAGGACAGTTTCTTACAGTAATTGGAGCATTTT3240               GGCATCTAACAAAGGAGAGGAAATATATATTCTCTGTAAGAATGGCCCTAGTAAATTGCC3300               TTAAAACTTTGCTTGAGGCTGATCCTTATTCAAAATGGGCCATTCTTAATGTAATGGGAA3360               AAGACTTTCCTGTAAATGAAGTATTTACACAATTTCTTGCTGACAATCATCACCAAGTTC3420               GCATGTTGGCTGCAGAGTCAATCAATAGATTGTTCCAGGACACGAAGGGAGATTCTTCCA3480               GGTTACTGAAAGCACTTCCTTTGAAGCTTCAGCAAACAGCTTTTGAAAATGCATACTTGA3540               AAGCTCAGGAAGGAATGAGAGAAATGTCCCATAGTGCTGAGAACCCTGAAACTTTGGATG3600               AAATTTATAATAGAAAATCTGTTTTACTGACGTTGATAGCTGTGGTTTTATCCTGTAGCC3660               CTATCTGCGAAAAACAGGCTTTGTTTGCCCTGTGTAAATCTGTGAAAGAGAATGGATTAG3720               AACCTCACCTTGTGAAAAAGGTTTTAGAGAAAGTTTCTGAAACTTTTGGATATAGACGTT3780               TAGAAGACTTTATGGCATCTCATTTAGATTATCTGGTTTTGGAATGGCTAAATCTTCAAG3840               ATACTGAATACAACTTATCTTCTTTTCCTTTTATTTTATTAAACTACACAAATATTGAGG3900               ATTTCTATAGATCTTGTTATAAGGTTTTGATTCCACATCTGGTGATTAGAAGTCATTTTG3960               ATGAGGTGAAGTCCATTGCTAATCAGATTCAAGAGGACTGGAAAAGTCTTCTAACAGACT4020               GCTTTCCAAAGATTCTTGTAAATATTCTTCCTTATTTTGCCTATGAGGGTACCAGAGACA4080               GTGGGATGGCACAGCAAAGAGAGACTGCTACCAAGGTCTATGATATGCTTAAAAGTGAAA4140               ACTTATTGGGAAAACAGATTGATCACTTATTCATTAGTAATTTACCAGAGATTGTGGTGG4200               AGTTATTGATGACGTTACATGAGCCAGCAAATTCTAGTGCCAGTCAGAGCACTGACCTCT4260               GTGACTTTTCAGGGGATTTGGATCCTGCTCCTAATCCACCTCATTTTCCATCGCATGTGA4320               TTAAAGCAACATTTGCCTATATCAGCAATTGTCATAAAACCAAGTTAAAAAGCATTTTAG4380               AAATTCTTTCCAAAAGCCCTGATTCCTATCAGAAAATTCTTCTTGCCATATGTGAGCAAG4440               CAGCTGAAACAAATAATGTTTATAAGAAGCACAGAATTCTTAAAATATATCACCTGTTTG4500               TTAGTTTATTACTGAAAGATATAAAAAGTGGCTTAGGAGGAGCTTGGGCCTTTGTTCTTC4560               GAGACGTTATTTATACTTTGATTCACTATATCAACCAAAGGCCTTCTTGTATCATGGATG4620               TGTCATTACGTAGCTTCTCCCTTTGTTGTGACTTATTAAGTCAGGTTTGCCAGACAGCCG4680               TGACTTACTGTAAGGATGCTCTAGAAAACCATCTTCATGTTATTGTTGGTACACTTATAC4740               CCCTTGTGTATGAGCAGGTGGAGGTTCAGAAACAGGTATTGGACTTGTTGAAATACTTAG4800               TGATAGATAACAAGGATAATGAAAACCTCTATATCACGATTAAGCTTTTAGATCCTTTTC4860               CTGACCATGTTGTTTTTAAGGATTTGCGTATTACTCAGCAAAAAATCAAATACAGTAGAG4920               GACCCTTTTCACTCTTGGAGGAAATTAACCATTTTCTCTCAGTAAGTGTTTATGATGCAC4980               TTCCATTGACAAGACTTGAAGGACTAAAGGATCTTCGAAGACAACTGGAACTACATAAAG5040               ATCAGATGGTGGACATTATGAGAGCTTCTCAGGATAATCCGCAAGATGGGATTATGGTGA5100               AACTAGTTGTCAATTTGTTGCAGTTATCCAAGATGGCAATAAACCACACTGGTGAAAAAG5160               AAGTTCTAGAGGCTGTTGGAAGCTGCTTGGGAGAAGTGGGTCCTATAGATTTCTCTACCA5220               TAGCTATACAACATAGTAAAGATGCATCTTATACCAAGGCCCTTAAGTTATTTGAAGATA5280               AAGAACTTCAGTGGACCTTCATAATGCTGACCTACCTGAATAACACACTGGTAGAAGATT5340               GTGTCAAAGTTCGATCAGCAGCTGTTACCTGTTTGAAAAACATTTTAGCCACAAAGACTG5400               GACATAGTTTCTGGGAGATTTATAAGATGACAACAGATCCAATGCTGGCCTATCTACAGC5460               CTTTTAGAACATCAAGAAAAAAGTTTTTAGAAGTACCCAGATTTGACAAAGAAAACCCTT5520               TTGAAGGCCTGGATGATATAAATCTGTGGATTCCTCTAAGTGAAAATCATGACATTTGGA5580               TAAAGACACTGACTTGTGCTTTTTTGGACAGTGGAGGCACAAAATGTGAAATTCTTCAAT5640               TATTAAAGCCAATGTGTGAAGTGAAAACTGACTTTTGTCAGACTGTACTTCCATACTTGA5700               TTCATGATATTTTACTCCAAGATACAAATGAATCATGGAGAAATCTGCTTTCTACACATG5760               TTCAGGGATTTTTCACCAGCTGTCTTCGACACTTCTCGCAAACGAGCCGATCCACAACCC5820               CTGCAAACTTGGATTCAGAGTCAGAGCACTTTTTCCGATGCTGTTTGGATAAAAAATCAC5880               AAAGAACAATGCTTGCTGTTGTGGACTACATGAGAAGACAAAAGAGACCTTCTTCAGGAA5940               CAATTTTTAATGATGCTTTCTGGCTGGATTTAAATTATCTAGAAGTTGCCAAGGTAGCTC6000               AGTCTTGTGCTGCTCACTTTACAGCTTTACTCTATGCAGAAATCTATGCAGATAAGAAAA6060               GTATGGATGATCAAGAGAAAAGAAGTCTTGCATTTGAAGAAGGAAGCCAGAGTACAACTA6120               TTTCTAGCTTGAGTGAAAAAAGTAAAGAAGAAACTGGAATAAGTTTACAGGATCTTCTCT6180               TAGAAATCTACAGAAGTATAGGGGAGCCAGATAGTTTGTATGGCTGTGGTGGAGGGAAGA6240               TGTTACAACCCATTACTAGACTACGAACATATGAACACGAAGCAATGTGGGGCAAAGCCC6300               TAGTAACATATGACCTCGAAACAGCAATCCCCTCATCAACACGCCAGGCAGGAATCATTC6360               AGGCCTTGCAGAATTTGGGACTCTGCCATATTCTTTCCGTCTATTTAAAAGGATTGGATT6420               ATGAAAATAAAGACTGGTGTCCTGAACTAGAAGAACTTCATTACCAAGCAGCATGGAGGA6480               ATATGCAGTGGGACCATTGCACTTCCGTCAGCAAAGAAGTAGAAGGAACCAGTTACCATG6540               AATCATTGTACAATGCTCTACAATCTCTAAGAGACAGAGAATTCTCTACATTTTATGAAA6600               GTCTCAAATATGCCAGAGTAAAAGAAGTGGAAGAGATGTGTAAGCGCAGCCTTGAGTCTG6660               TGTATTCGCTCTATCCCACACTTAGCAGGTTGCAGGCCATTGGAGAGCTGGAAAGCATTG6720               GGGAGCTTTTCTCAAGATCAGTCACACATAGACAACTCTCTGAAGTATATATTAAGTGGC6780               AGAAACACTCCCAGCTTCTCAAGGACAGTGATTTTAGTTTTCAGGAGCCTATCATGGCTC6840               TACGCACAGTCATTTTGGAGATCCTGATGGAAAAGGAAATGGACAACTCACAAAGAGAAT6900               GTATTAAGGACATTCTCACCAAACACCTTGTAGAACTCTCTATACTGGCCAGAACTTTCA6960               AGAACACTCAGCTCCCTGAAAGGGCAATATTTCAAATTAAACAGTACAATTCAGTTAGCT7020               GTGGAGTCTCTGAGTGGCAGCTGGAAGAAGCACAAGTATTCTGGGCAAAAAAGGAGCAGA7080               GTCTTGCCCTGAGTATTCTCAAGCAAATGATCAAGAAGTTGGATGCCAGCTGTGCAGCGA7140               ACAATCCCAGCCTAAAACTTACATACACAGAATGTCTGAGGGTTTGTGGCAACTGGTTAG7200               CAGAAACGTGCTTAGAAAATCCTGCGGTCATCATGCAGACCTATCTAGAAAAGGCAGTAG7260               AAGTTGCTGGAAATTATGATGGAGAAAGTAGTGATGAGCTAAGAAATGGAAAAATGAAGG7320               CATTTCTCTCATTAGCCCGGTTTTCAGATACTCAATACCAAAGAATTGAAAACTACATGA7380               AATCATCGGAATTTGAAAACAAGCAAGCTCTCCTGAAAAGAGCCAAAGAGGAAGTAGGTC7440               TCCTTAGGGAACATAAAATTCAGACAAACAGATACACAGTAAAGGTTCAGCGAGAGCTGG7500               AGTTGGATGAATTAGCCCTGCGTGCACTGAAAGAGGATCGTAAACGCTTCTTATGTAAAG7560               CAGTTGAAAATTATATCAACTGCTTATTAAGTGGAGAAGAACATGATATGTGGGTATTCC7620               GGCTTTGTTCCCTCTGGCTTGAAAATTCTGGAGTTTCTGAAGTCAATGGCATGATGAAGA7680               GAGACGGAATGAAGATTCCAACATATAAATTTTTGCCTCTTATGTACCAATTGGCTGCTA7740               GAATGGGGACCAAGATGATGGGAGGCCTAGGATTTCATGAAGTCCTCAATAATCTAATCT7800               CTAGAATTTCAATGGATCACCCCCATCACACTTTGTTTATTATACTGGCCTTAGCAAATG7860               CAAACAGAGATGAATTTCTGACTAAACCAGAGGTAGCCAGAAGAAGCAGAATAACTAAAA7920               ATGTGCCTAAACAAAGCTCTCAGCTTGATGAGGATCGAACAGAGGCTGCAAATAGAATAA7980               TATGTACTATCAGAAGTAGGAGACCTCAGATGGTCAGAAGTGTTGAGGCACTTTGTGATG8040               CTTATATTATATTAGCAAACTTAGATGCCACTCAGTGGAAGACTCAGAGAAAAGGCATAA8100               ATATTCCAGCAGACCAGCCAATTACTAAACTTAAGAATTTAGAAGATGTTGTTGTCCCTA8160               CTATGGAAATTAAGGTGGACCACACAGGAGAATATGGAAATCTGGTGACTATACAGTCAT8220               TTAAAGCAGAATTTCGCTTAGCAGGAGGTGTAAATTTACCAAAAATAATAGATTGTGTAG8280               GTTCCGATGGCAAGGAGAGGAGACAGCTTGTTAAGGGCCGTGATGACCTGAGACAAGATG8340               CTGTCATGCAACAGGTCTTCCAGATGTGTAATACATTACTGCAGAGAAACACGGAAACTA8400               GGAAGAGGAAATTAACTATCTGTACTTATAAGGTGGTTCCCCTCTCTCAGCGAAGTGGTG8460               TTCTTGAATGGTGCACAGGAACTGTCCCCATTGGTGAATTTCTTGTTAACAATGAAGATG8520               GTGCTCATAAAAGATACAGGCCAAATGATTTCAGTGCCTTTCAGTGCCAAAAGAAAATGA8580               TGGAGGTGCAAAAAAAGTCTTTTGAAGAGAAATATGAAGTCTTCATGGATGTTTGCCAAA8640               ATTTTCAACCAGTTTTCCGTTACTTCTGCATGGAAAAATTCTTGGATCCAGCTATTTGGT8700               TTGAGAAGCGATTGGCTTATACGCGCAGTGTAGCTACTTCTTCTATTGTTGGTTACATAC8760               TTGGACTTGGTGATAGACATGTACAGAATATCTTGATAAATGAGCAGTCAGCAGAACTTG8820               TACATATAGATCTAGGTGTTGCTTTTGAACAGGGCAAAATCCTTCCTACTCCTGAGACAG8880               TTCCTTTTAGACTCACCAGAGATATTGTGGATGGCATGGGCATTACGGGTGTTGAAGGTG8940               TCTTCAGAAGATGCTGTGAGAAAACCATGGAAGTGATGAGAAACTCTCAGGAAACTCTGT9000               TAACCATTGTAGAGGTCCTTCTATATGATCCACTCTTTGACTGGACCATGAATCCTTTGA9060               AAGCTTTGTATTTACAGCAGAGGCCGGAAGATGAAACTGAGCTTCACCCTACTCTGAATG9120               CAGATGACCAAGAATGCAAACGAAATCTCAGTGATATTGACCAGAGTTTCGACAAAGTAG9180               CTGAACGTGTCTTAATGAGACTACAAGAGAAACTGAAAGGAGTGGAAGAAGGCACTGTGC9240               TCAGTGTTGGTGGACAGGTGAATTTGCTCATACAGCAGGCCATAGACCCCAAAAATCTCA9300               GCCGACTTTTCCCAGGATGGAAAGCTTGGGTGTGATCTTCAGTATATGAATTACCCTTTC9360               ATTCAGCCTTTAGAAATTATATTTTAGCCTTTATTTTTAACCTGCCAACATACTTTAAGT9420               AGGGATTAATATTTAAGTGAACTATTGTGGGTTTTTTTGAATGTTGGTTTTAATACTTGA9480               TTTAATCACCACTCAAAAATGTTTTGATGGTCTTAAGGAACATCTCTGCTTTCACTCTTT9540               AGAAATAATGGTCATTCGGGCTGGGCGCAGCGGCTCACGCCTGTAATCCCAGCACTTTGG9600               GAGGCCGAGGTGAGCGGATCACAAGGTCAGGAGTTCGAGACCAGCCTGGCCAAGAGACCA9660               GCCTGGCCAGTATGGTGAAACCCTGTCTCTACTAAAAATACAAAAATTAGCCGAGCATGG9720               TGGCGGGCACCTGTAGTCCCAGCTACTCGAGAGGCTGAGGCAGGAGAATCTCTTGAACCT9780               GGGAGGTGAAGGTTGCTGTGGGCCAAAATCATGCCATTGCACTCCAGCCTGGGTGACAAG9840               AGCGAAACTCCATCTCAAAAAAAAAAAAAA9870                                             __________________________________________________________________________ 

We claim:
 1. A purified and isolated cDNA having a sequence selected from the group consisting of SEO ID No:1, SEQ ID No:3 and SEQ ID No:9, mutations in which cause ataxia-telangiectasia.
 2. A purified and isolated mRNA having a sequence complementary to said sequences of claim
 1. 3. A purified and isolated cDNA having a sequence which is set forth in SEO ID No:3.
 4. A purified and isolated cDNA having a sequence which is set forth in SEQ ID No:9.
 5. A purified and isolated cDNA which differs from that of claim 1 due to a mutation event selected from the group consisting of point mutations, deletions, insertions and rearrangements, such that the encoded amino acid sequence is altered from that encoded by SEQ ID No:
 1. 3 or
 9. imparting ataxia-telangiectasia.
 6. The cDNA of claim 5 wherein the mutations are as set forth in Table 1 which contains a listing of mutations which cause protein truncation and thereby ataxia-telangiectasia.
 7. A vector comprising an expression control sequence operatively linked to the cDNA of claim
 1. 8. A vector comprising an expression control sequence operatively linked to a cDNA as set forth in claim
 5. 9. A host cell which is transformed with the vector of claim 7, wherein said host cell is selected from the group consisting of suitable eucaryotic and procaryotic cells for expressing said vector.
 10. A host cell which is transformed with the vector of claim 8, wherein said host cell is selected from the group consisting of suitable eucaryotic and procaryotic cells for expressing said vector.
 11. The host cell of claim 9 wherein said host cell is E. coli.
 12. A cell line containing a cDNA of claim 1 which is operatively linked to an expression control sequence appropriate for said cell line.
 13. A cell line containing a cDNA of claim 3 which is operatively linked to an expression control sequence appropriate for the cell line.
 14. A cell line containing a cDNA of claim 4 which is operatively linked to an expression control sequence appropriate for said cell line.
 15. A cell line containing a cDNA of claim 6 which is operatively linked to an expression control sequence appropriate for said cell line. 